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Anti Cancer
Chemotherapy
• Cancer
– Uncontrolled multiplication and spread within the
body of abnormal forms of body's own cells
• Neoplasm
– A mass of tissue formed as a result of
• Abnormal
• Excessive
• Uncoordinated
• Autonomous and
• purposeless
Proliferation of cells
Cancer chemotherapy not as successful as
antimicrobial chemotherapy
• Metabolism in parasite differs qualitatively
from host cells, while metabolism in cancer
cells differ only quantitatively from normal host
cells
– Hence target selectivity is more difficult in cancer
– cancer there is no substantial immune response
– Diagnostic complexity: delay in institution of
treatment
Modalities of treatment in cancer
• Surgery
• Radiotherapy
• Chemotherapy: 50 % of the patients can be
treated with chemotherapy contributing to
cure in 15 -20 % of patients
1/3 of patients can be cured, effective
when tumor has not metastasized
Cancer chemotherapy can be curative in
• Acute Leukemias
• Wilm’s Tumour
• Ewing’s Sarcoma
• Choriocarcinoma
• Hodgkin’s Disease
• Lymphosarcoma
• Burkitts lymphoma
• Testicular Teratomas
• Seminomas
In children
Chemotherapy can have only Palliative effect in
• Breast Cancer
• Ovarian Cancer
• Endometrial Cancer
• Prostatic Cancer
• Chronic Lymphatic Leukemia
• Chronic Myeloid Leukemia
• Head & Neck Cancer
• Lung (small cell) Cancer
Chemotherapy is less sensitive in
• Colorectal Cancer
• Carcinoma Stomach
• Carcinoma of esophagus
• Renal carcinoma
• Hepatoma
• Bronchogenic (non small cell) carcinoma
• Malignant Melanoma
• Sarcoma
Pathogenesis of cancer
Chemicals, viruses, irradiation, etc
Acquired Mutations
Protooncogenes  oncogenes ↓ expression of tumor
supressor genes (P53, Rb etc)
Promoters,
co-carcinogen,
hormones
Uncontrolled cell
proliferation,
dedifferentiation
↓ apoptosis, alterations
in telomerase
Inherited Mutations
Development of primary tumor
Pathogenesis of cancer
Development of primary tumor
Production of metalloproteinases
Invasion of nearby tissue by tumor cells
Angiogenesis
Metastasis
Development of secondary tumors
Cancer cells differ from normal cells by
• Uncontrolled proliferation
• De-differentiation & loss of function
• Invasiveness
• Metastasis
Guiding principles in cancer
chemotherapy
• To achieve cure a TOTAL CELL KILL must be
tried
• Early diagnosis and early institution of
treatment
• Combination chemotherapy
• Intermittent regimens
• Adjuvant and neoadjuvant chemotherapy
occasionally
Total cell kill
• Aimed at destroying all the malignant cells,
leaving none
• This approach ensures
– Early recovery
– Prevents relapse
– Prolongs survival
• Pharmacological sancturies
Effects of various T/t on cancer cell burden
• Survival time inversely related to initial
number of cells
• Aging cancer cells are less susceptible to
chemotherapy, because there is
– ↑ cell cycle (division) time
– ↓No of actively dividing cells with more resting
cells
– ↑ cell death within tumor
– Overcrowding of cells
Combination chemotherapy?
• Heterogenicity of cells remaining in different
phase of growth cycle , showing different level
of sensitivity
– Nature of drug (with different biochemical site of
action)
– Avoid emergence of drug resistance
• Monotherapy adequate in Burkitts lymphoma
& choriocarcinoma
Why intermittent regimen?
• Favours risk –benefit ratio
• Allows time for damaged normal host cells to
recover
• Pulse therapy
– Type of intermittent chemotherapeutic regime
employing highest tolerated dose within a short
administration period
– Based on principle of drug conc. (C) x duration of
exposure (T) = constant
Adjuvant & Neoadjuvant chemotherapy
• Adjuvant chemotherapy:
– Chemotherapy given after surgery or irradiation to
destroy micrometastasis & prevent development of
secondary neoplasm.
• Neo-adjuvant chemotherapy:
– Chemotherapy given before surgery or
radiotherapy in order to diminish the volume of
large primary neoplasm
• Nausea & Vomiting
• Bone marrow depression
• Alopecia
• Gonads: Oligospermia, impotence, ↓ ovulation
• Foetus: Abortion, foetal death, teratogenicity
• Carcinogenicity
• Hyperuricemia
• Immunosupression: Fludarabine
• Hazards to staff
General toxicity of cytotoxic drugs
Phases of cell cycle
CLASSIFICATION - I:
CELL CYCLE NON SPECIFIC :
Kills resting cells & dividing
cells
• Cyclophosphamide
• Chlorambucil
• Cisplatin
• Actinomycin-D
• L-asparaginase
CELL CYCLE SPECIFIC
Kills actively dividing cells
• G1 – Vinblastine
• S – Methotrexate
6-Mercaptopurine
5-Fluorouracil
• G2 –Bleomycin
Etoposide, Topotecan
Daunorubicin
• M – Vincristine
Vinblastine
Paclitaxel,Docetaxel
CLASSIFICATION - II:
Depending on mechanism at cell level
• Directly acting cytotoxic drugs:
– Alkylating agents
– Antimetabolites
– Natural products
• Antibiotics
• Vinca alkaloids
• Taxanes
• Epipodophyllotoxins
• Camptothecin analogs
• Enzymes
• Biological response
modifiers
– Miscellaneous: Cisplatin,
carboplatin
• Indirectly acting- by
altering the hormonal
mileau :
– Corticosteroids
– Estrogens & ERMs
– 5 alpha reductase
inhibitors
– Gnrh agonists
– Progestins
• Nitrogen Mustards
– Meclorethamine, Melphalan, Chlorambucil,
cyclophosphamide, ifosfamide
• Ethyleneimine : Thiotepa
• Alkyl Sulfonate: Busulfan
• Nitrosureas
– Carmustine,lomustine, streptozocin
• Triazines
– Dacarbazine, temozolamide
Alkylating agents
• Folate Antagonists
– Methotrexate
• Purine Antagonists
– 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
– 5 Fluorouracil, cytarabine, gemcitabine
Antimetabolites
• Antibiotics
– Actinomycin D,
Doxorubicin,
Daunorubicin, Bleomycin,
Mitomycin C
• Vinca alkaloids
– Vincristine, Vinblastine,
Vinorelbine
• Taxanes
– Paclitaxel, docetaxel
• Enzymes
– L-Asparginase
Natural Products
• Epipodophyllotoxins
– etoposide,
tenoposide
• Camptothecin
analogs
– Topotecan, irinotecan
• Biological response
modifiers
– Interferons,
– Interleukins
• Cisplatin
• Carboplatin
• Hydroxurea
• Procarbazine
• Mitotane
• Imatinib
Miscellaneous Agents
Hormones & antagonists
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifene, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide
MOA of some anticancer drugs
Purine & Pyrimidine synthesis
Ribonucleotides
Deoxy ribonucleotides
DNA
RNA
Proteins
Purine/
Pyrimidine
antagonists Methotrexate
Inhibition of
purine ring &
dTMP
biosynthesis
5 FU inhibits
dTMP synthesis
Dactinomycin ,
Intercalate with DNA
disrupt DNA function
Alkylating agents
Alter structure &
function of DNA
by cross linking
and/or
fragmenting DNA
Cytarabine inhibits
DNA chain elongation
Alkylating agents
• Nitrogen Mustards (MCI)
– Meclorethamine, Melphalan, Chlorambucil,
Cyclophosphamide, Ifosfamide
• Ethyleneimine : Thiotepa
• Alkyl Sulfonate: Busulfan
• Nitrosureas
– Carmustine,lomustine, streptozocin
• Triazines
– Dacarbazine, temozolamide
Mechanism of action
Alkylating Agents
Form highly reactive carbonium ion
Transfer alkyl groups to nucleophilic sites on DNA bases
Results in
Cross linkage Abnormal base pairing DNA strand breakage
↓ cell proliferation
Alkylation also damages RNA
and proteins
Cancer chemotherapy
• Cytotoxic action
– Hemopoetic system highly susceptible
• Chlorambucil – more against lymphoid series
• Busulfan – more against myeloid series
– Epithelial tissues, hair follicles
– Spermatogenesis , fetopathic effect
• Immunosupressant action
• Miscellaneous
– Severe nausea & vomiting
• Known as radiomimetic drugs
Pharmacological actions
• Mechlorethamine
• Melphalan
• Chlorambucil
• Cyclophosphamide
• Ifosfamide
Nitrogen Mustards
• Very irritant drug
• Dose = 0.4 mg/kg single or divided
• Uses
– Hematological cancers , lymphomas , solid tumors
• Adverse effects
– Anorexia, nausea, vomiting
– Bone marrow depression, aplasia
– Menstrual irregularities
• Estramustine
Mechlorethamine (Mustine)
Melphalan
• Very effective in MULTIPLE MYELOMA
• Less irritant locally , less alopecia
• Dose:
0.25 mg/kg daily for 4 days every 4-6 weeks
• Adverse Effects :
– Bone marrow Depression
– Infections , diarrhoea and pancreatitis
• Most commonly used alkylating agent a prodrug
Cyclophosphamide
Cyclophosphamide
Cyclophosphamide
Aldophosphamide
Phosphoramide
mustard
Acrolein
Cytotoxic effect
Hemorrhagic cystitis
Mesna

Uses of cyclophosphamide
• Neoplastic conditions
– Hodgkins and non hodgkins lymphoma
– ALL (Acute Lymphoblastic leukemia), CLL (Chronic
Lymphocytic leukemia), Multiple myeloma
– Burkits lymphoma
– Neuroblastoma , retinoblastoma
– Adenocarcinoma of ovaries
• Non neoplastic conditions
– Control of graft versus host reaction
– Rheumatoid arthritis
– Nephrotic syndrome
• Adverse effects:
– Hemorrhagic cystitis,
– alopecia,
– nausea & vomiting,
– SIADH
– hepatic damage
• Dose: 2-3 mg/kg/day oral
10-15 mg/kg IV every 7-10 days
• It can be administered IV, IM, IP, intrapleurally,
Intraarterialy, directly into tumor
Cyclophosphamide
Ifosfamide
• Congener of cyclophosphamide
• Longer half life than cyclophosphamide
• Less alopecia and less emetogenic than
cyclophosphamide
• Can cause hemorrhagic cystitis and severe
neurological toxicity
• Used for germ cell testicular tumors and adult
sarcomas
Chlorambucil (Leukeran)
• Slowest acting and least toxic alkylating agent
• Main action on lymphoid series produces
marked lympholytic action
• Drug of choice for long term maintenance
therapy of CLL
• Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2
mg daily for maintenance
ThioTEPA
• Triethylene phosphoramide
• Does not require to form active intermediate
• Active intravesicular agent can also be used
topicaly in superficial bladder cancer
• Not well absorbed orally given IV
• High toxicity
Busulfan (Myleran)
• Depresses bone marrow with selective action
on myeloid series
• Primarily used in Chronic myelogenous
leukemia 2-6 mg/day
• Adverse effect:
– Interstitial pulmonary fibrosis
– Venoocclusive disease of liver
– Hyperuricaemia
– Sterility
Nitrosureas
• Highly lipid soluble, Cross BBB
• Uses:
– Meningeal / Brain tumours
• Dose :150-200 mg/m2 BSA
every 6 wks (Carmustine)
• Adverse Effects:
– Delayed bone marrow
suppression
– Visceral fibrosis, renal
damage
Triazenes
• Dacarbazine
– Primary inhibitory action on RNA
& protein synthesis
– Used in malignant melanoma
• Temozolamide
– New alkylating agent
– Approved for malignant glioma
– Rapidly absorbed after oral
absorption & crosses BBB
Mechanisms of resistance of alkylating
agents
• ↓ Influx of drug
• ↑ Production of nucleophilic substances like
glutathione that compete with target DNA for
alkylation
• ↑ Activity of DNA repair enzymes
• ↑ metabolic inactivation of drugs
Cisplatin
• Non cell cycle specific
killing
• Administered IV
• Highly bound to plasma
proteins
• Gets conc in kidney,
intestine, testes
• Poorly penetrates BBB
• Slowly excreted in urine
Pt
NH3Cl
Cl NH3
Dose:
20 mg/m2 for 5 days a
week
75 – 100 mg/m2 once in
4 weeks to treat ovarian
cancer
Mechanism of action of cisplatin
Cisplatin enters cells
Forms highly reactive platinum complexes
DNA damage
Intra strand & interstrand cross links
Inhibits cell proliferation
Cisplatin uses and adverse effects
• Uses
– Testicular cancer (85% - 95 % curative )
– Ovarian cancer
– Other solid tumors: lung, esophagus, gastric
• Adverse effects
– Emesis
– Nephrotoxicity
– Peripheral neuropathy
– Ototoxicity
Carboplatin
• Better tolerated
• Nephrotoxicity , ototoxicity , neurotoxicity low
• Less emetogenic
• But thrombocytopenia and leukopenia may
occur
• Less plasma protein binding
• Use:
– primarily in ovarian cancer of epithelial origin
– Squamous cell carcinoma of head and neck
Antimetabolites
• Folate Antagonists
– Methotrexate
• Purine Antagonists
– 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
– 5 Fluorouracil, cytarabine, gemcitabine
Methotrexate
Adenine, guanine,
thymidine ,
methionine, serine
Folic acid not
useful in toxicity
Folinic acid N5
formyl FH4 should be
given which is
converted to N5,N10-
Methylene –FH4 and
bypasses the
inhibited reductase
Pharmacological actions
• Cytotoxic actions
– Predominant on bone marrow
– Ulceration of intestinal mucosa
– Crosses placenta interferes with embroyogenesis
foetal malformations and death
• Immunosupressive action
– Prevents clonal expansion of B & T lymphocytes
• Anti-Inflammatory action
– Interferes with release of inflammatory cytokines
IL-2, IL-6,IL-8 & TNF- , ↓ Rheumatoid Factor
production
Pharmacokinetics
• Absorbed orally, 50 %
protein bound
• Disappears rapidly
from blood , remains
in tissue longer than
folate thus causes
prolonged inhibitory
effect
• C/I in renal
impairment
Adverse effects
• Megaloblastic anemia
• Thrombocytopenia, leukopenia, aplasia
• Oral, intestinal ulcer , diarrhoea
• Alopecia , liver damage, nephrpathy
 Folinic acid (citrovorum factor, N5 Formyl THF)
 IM/IV 8 to 24 hrs after initiation of methotrexate
 120 mg in divided doses in first 24 hrs, then 25
mg oral/IM 6 hrly for next 48 hrs
Treatment of methotrexate toxicity
Uses of methotrexate
• Antineoplastic
– Choriocarcinoma and tropoblast tumor
15 -30 mg/day orally for 5 days
– Remission of ALL in children 2.5 to 15 mg/day
– Ca breast, head & neck, bladder, ovarian cancer
• Immuno-supressive agent
– Rheumatoid arthritis, resistant asthma
– Crohns disease, wegeners granulomatosis
– Prevention of graft versus host reaction
• Psoriasis
• Medical termination of pregnancy
• 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
• Fludarabine
Purine antagonists
6 Mercaptopurine
6 MP
6 Thiouric acid
Xanthine oxidase
Allopurinol
TPMT
Inactive
metabolite
• Use:
– Acute leukemia (ALL)
– Choriocarcinoma
• Adverse Effects:
– Bone marrow & GIT mainly
– Hepatic necrosis rarely
– Hyperuricaemia
6 Mercaptopurine
• Phosphorylates intracellularly to form
triphosphate
• Inhibits DNA polymerase and gets incorporated
to form dysfunctional DNA
• Effective in slow growing tumors: (apoptosis)
• Use:
– CLL and non hodgkins recurring after treatment
• Adverse events:
– chills, fever, opportunistic infection,
myelosupression
Fludarabine
• Like fludarabine converted to triphosphate
• Incorporated into DNA
• Inhibits DNA polymerase  and  thus inhibits
DNA synthesis and repair
• Used in treatment of Hairy cell leukemia, CLL
and low grade lymphomas
Cladirabine
Pentostatin
Inhibits adenosine deaminase
Accumulation of adenosine & deoxyadenosine
Inhibits ribonucleotide reductase
Blocks DNA synthesis
S adenosyl homocysteine accumulation
Toxic to lymphocytes Used in
Hairy cell leukemia
• 5 fluoruracil
• Cytosine arabinoside (Cytarabine)
• Gemcitabine
Pyrimidine antagonists
5 fluorouracil
5 FU FdUMP
dUMP
Thymidine
Monophosphate
Thymidilate
synthetase
DNA Synthesis
(Selective failure)
Uses : stomach , colon,
breast ovaries , liver, skin
cancers
FdUMP = fluorodeoxyuridine
monophosphate
• Pyrimidine analog considered drug of choice
in inducing remission in AML
• Phosphorylated in body to triphosphate
• Triphosphate of cytarabine inhibits DNA
polymerase  & 
• Thus inhibit DNA synthesis and repair
Cytosine arabinoside
Gemcitabine
• Drug of choice in adenocarcinoma of pancreas
• Obtained from periwinkle plant ( Vinca Rosea)
• Vincristine, vinblastine, vindesine, vinorelbine
Vinca alkaloids
Mechanism of action
Comparison between
Vincristine
• Marrow sparing effect
• Alopecia more common
• Peripheral & autonomic
neuropathy & muscle
weakness (CNS)
• Constipation
• Uses: (Childhood cancers)
– ALL , Hodgkins, lymphosarcoma,
Wilms tumor, Ewings sarcoma
Vinblastine
• Bone marrow supression
• Less common
• Less common, temp.
mental depresssion
• Nausea, vomiting,
diarrhoea
• uses
– Hodgkins disease & other
lymphomas , breast cancer,
testicular cancer
Taxanes
• Paclitaxel & docetaxel
• Plant product obtained from bark of Pacific
Yew ( Taxus Brevifolia) & European Yew (Taxus
Buccata)
Mechanism of action
Cell cycle arrested in G2 and M phase
• Paclitaxel
– Administered IV
– Use: advanced breast & ovarian cancer also lungs,
esophagus, prostrate cancer
– Adverse effects:
• Anaphylactoid reaction because of solvent cremaphor
• Myalgia, myelosupression, peripheral neuropathy
• Docetaxel
– Oral
– Used in refractory breast & ovarian cancer
– Major toxicity neutropenia may cause
aarrhythmias , hypotension
Epipodophyllotoxins
• Etoposide & tenoposide
• Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum (plant glycoside)
Etoposide
• Act in S & G2 phase
• Inhibit topoisomerase II which results in
breakage of DNA strands & cell death
• Uses:
– Testicular tumors , squamous cell cancer of lungs
• Derived from camptotheca accuminata
• Inhibit Topoisomerase I: No resealing of DNA
after strand has untwisted
• Topotecan:
– Used in metastatic ovarian cancer
– Major toxicity is bone marrow depression
• Irinotecan
– Used in metastatic cancer of colon/rectum
– Toxicity: diarrhoea, neutropenia, thrombocytopenia,
cholinergic side effects
Camptothecin analogs
• Cell cycle non specific drugs
• Derived from streptomyces species
• MOA:
– Intercalation in the DNA between adjoining
nucleotide pairs – blocks DNA & RNA synthesis
– Generation of oxygen radicals which mediate
single strand scission of DNA
– Action on Topoisomerase II
Anticancer antibiotics
• Uses:
– Wilms tumor,
– gestational choriocarcinoma
• Adverse effects
– bone marrow supression
– Irritant like meclorethamine
– sensitizes to radiation, and
inflammation at sites of prior
radiation therapy may occur
– Gastrointestinal adverse effects
Dactinomycin
Doxorubicin & Daunorubucin
• Doxorubicin:
– Used in acute leukemias, malignant lymphoma
and many solid tumors, direct instillation in
bladder cancer
• Daunorubicin:
– Use limited to ALL and granulocytic leukemias
• Toxicity:
– Both cause cardiotoxicity (cardiomyopathy)
– Marrow Depression, Alopecia
• Mitoxantrone
– Analog of doxorubicin
– Lower cardiotoxicity
– Uses: Acute leukemia, CML, Non hodgkins
• Mitomycin C
– Highly toxic used only in resistant cancers of
stomach, colon, rectum
– Transformed to form which acts like alkylating agent
• Mithramycin
– Reduces blood calcium levels by inhibiting
osteoclasts
– Used in T/t of hypercalcemia with bone metastasis
Bleomycin
Reacts with iron,
copper & O2 in
presence of CYP -450
reductase
Also can intercalate
between DNA strands
DNA – bleomycin – Fe2+
DNA – bleomycin – Fe3+
• Uses :
– Epidermoid cancers of skin, oral cavity,
genitourinary tract, esophagus
– Testicular tumors
– Hodgkins lymphoma
• Adverse effects:
– Pneumonitis
– Fatal pulmonary fibrosis
– Hyper pigmentation
– spares bone marrow
Bleomycin
L-asparaginase
L-asparaginase
• Isolated from E.coli
• Use: Acute Lymphocytic Leukemia (ALL)
• Dose :
• 6000 to 10000U/kg IV daily for 3-4 weeks
• A/E:
• Hepatic damage
• Hypersensitivity , hemorrhage
• Hyperglycemia, headache, hallucinations ,
confusion, coma
Hydroxyurea
• Uses:
• CML, Polycythemia,
psoriasis
• Dose:
• 20-30 mg/kg /day
orally
Ribonucleotides Deoxyribonucleotides
Ribonucleoside diphosphate
reductase
Hydroxyurea
• Adverse effects
• Myelosuppression
(Minimal)
• Hypersensitivity
• Hyperglycemia
• Hypoalbuminemia
Procarbazine
• MOA: Depolymerizes DNA & causes
chromosomal damage
• USES: Hodgkin’s disease ( MOPP regimen)
• Non hodgkins lymphoma
• 100-200mg daily orally
• A/e: MAO inhibitor action & antabuse action
Radio active isotopes
• I131 – Emits beta radiation , half life-8.04 days
use:Follicular Ca- Thyroid
• P32 - Emits beta radiation , half life- 14.3 days.
use : Polycythemia vera
• 198Au – gives low energy beta & gamma
radiation, half life- 2.69 days
use :malignant pleural, peritoneal effusion
Hormones & antagonists
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifene, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide
Glucocorticoids
• Marked lympholytic effect so used in acute
leukaemias & lymphomas,
• They also
– Have Anti-inflammatory effect
– Increase appetite, prevent anemia
– Produce sense of well being
– Increase body weight
– Supress hypersensitivity reaction
– Control hypercalcemia & bleeding
– Non specific antipyretic effect
– Increase antiemetic effect of ondansetron
Estrogens
• Physiological antagonists of androgens
• Thus used to antagonize the effects of
androgens in androgen dependent prostatic
cancer
• Fofesterol
– Prodrug , phosphate derivative of stilbesterol
– 600-1200mg IV initially later 120-240 mg orally
• Tamoxifen : Non steroidal antiestrogen
Selective Estrogen Receptor Modulators
(SERMs)
Agonistic:
Uterus,
bone, liver,
pitutary
Antagonistic:
Breast and
blood vessels
Tamoxifen
• DOSE:10-20mg bd
• Standard hormonal
treatment in breast cancer
• Adverse effects:
– Hot flushes , vomiting, vaginal
bleeding, menstrual
irregularities, venous
thromboembolism,
dermatitis, rarely endometrial
cancer
• Pure estrogen antagonist
• USES: Metastatic ER+ Breast Ca in
postmenopausal women
• MOA:
• Inhibits ER dimerization & prevents interaction of
ER with DNA
• ER is down regulated resulting in more complete
supression of ER responsive gene function
Selective Estrogen Receptor Down regulator
(fulvestrant)
• Letrozole
• Orally active non steroidal compound
• MOA : Inhibits aromatisation of testosterone &
androstenedione to form estrogen.
• Uses : Breast Ca- & adj. to mastectomy
• Dose :2.5mg bd orally
• Anastrozole : more potent
• 1mg OD in ER+ Breast Ca
• A/E : hot flushes
Aromatase Inhibitors
• FLUTAMIDE & BICALUTAMIDE :
• Androgen Receptor antagonists
• Dose : 250 mg tds, 50mg od resp.
• Palliative effect in metastatic Prostatic Ca
after orchidectomy
Anti androgens
5- reductase inhibitors
Finasteride
• Orally active
• DHT levels ↓
• Benign prostatic
hyperplasia
Dose: 5mg/day
Prostate volume
Symptom score
Peak urine flow
rate
DHT level in
prostate
Side effects: Loss of libido & impotence in 5 % pts.
Also used for prevention of hair loss
• NAFERELIN : nasal spray / SC inj
• ↓FSH & LH release from pituitary- ↓ the
release of estrogen & testosterone
• USE : Breast Ca, Prostatic Ca
• PROGESTINS:
• Hydroxyprogesterone – used in metastatic
endometrial Ca.
• A/E: bleeding
GnRH agonists
Cancer chemotherapy
Cancer chemotherapy
Newer anticancer drugs
• Inhibitors of growth factors receptors
– Imatinib: CML (BCR-ABL gene)
– Gefitinib: Non small cell cancer of lungs (EGFR)
– Nilotinib : CML (Tyrosine kinase inhibitor)
– Dasatinib : CML (Tyrosine kinase inhibitor)
– Lapatinib : metastatic breast cancer (HER2/neu)
– Sunitinib : renal cell carcinoma (VEGF)
– Sorafinib : renal cell carcinoma (VEGF)
• Monoclonal antibodies
– Trastuzumab : breast cancer (HER2/neu)
– Bevacizumab: metastatic colon cancer (VEGF)
– Rituximab : non hodgkins lymphoma (CD-20)
– Panitumumab : metastatic colon cancer (EGFR)
– Alemtuzumab : CLL (CD 52 antigen)
– Iodine tositumonab : Non hodgkins (CD-20)
Newer anticancer drugs
Cancer chemotherapy
Important drug combinations
REGIMEN CANCER DRUGS
MOPP Hodgkins Mechlorethamine, oncovin,
prednisolone, procarbazine
ABVD Hodgkins Doxorubicin, bleomycin, vinblastine,
dacarbazine
CMF Breast Cyclophosphamide, methotrexate, 5-FU
CAF Breast Cyclophosphamide, doxorubicin, 5FU
ALL Vincristine, prednisolone, aspargine,
daunorubicin
AML Cytarabine, methotrexate
CML Hydroxyurea, interferon
Wilms Actinomycin, vincristine, doxorubicin
THANK YOU

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Cancer chemotherapy

  • 2. • Cancer – Uncontrolled multiplication and spread within the body of abnormal forms of body's own cells • Neoplasm – A mass of tissue formed as a result of • Abnormal • Excessive • Uncoordinated • Autonomous and • purposeless Proliferation of cells
  • 3. Cancer chemotherapy not as successful as antimicrobial chemotherapy • Metabolism in parasite differs qualitatively from host cells, while metabolism in cancer cells differ only quantitatively from normal host cells – Hence target selectivity is more difficult in cancer – cancer there is no substantial immune response – Diagnostic complexity: delay in institution of treatment
  • 4. Modalities of treatment in cancer • Surgery • Radiotherapy • Chemotherapy: 50 % of the patients can be treated with chemotherapy contributing to cure in 15 -20 % of patients 1/3 of patients can be cured, effective when tumor has not metastasized
  • 5. Cancer chemotherapy can be curative in • Acute Leukemias • Wilm’s Tumour • Ewing’s Sarcoma • Choriocarcinoma • Hodgkin’s Disease • Lymphosarcoma • Burkitts lymphoma • Testicular Teratomas • Seminomas In children
  • 6. Chemotherapy can have only Palliative effect in • Breast Cancer • Ovarian Cancer • Endometrial Cancer • Prostatic Cancer • Chronic Lymphatic Leukemia • Chronic Myeloid Leukemia • Head & Neck Cancer • Lung (small cell) Cancer
  • 7. Chemotherapy is less sensitive in • Colorectal Cancer • Carcinoma Stomach • Carcinoma of esophagus • Renal carcinoma • Hepatoma • Bronchogenic (non small cell) carcinoma • Malignant Melanoma • Sarcoma
  • 8. Pathogenesis of cancer Chemicals, viruses, irradiation, etc Acquired Mutations Protooncogenes  oncogenes ↓ expression of tumor supressor genes (P53, Rb etc) Promoters, co-carcinogen, hormones Uncontrolled cell proliferation, dedifferentiation ↓ apoptosis, alterations in telomerase Inherited Mutations Development of primary tumor
  • 9. Pathogenesis of cancer Development of primary tumor Production of metalloproteinases Invasion of nearby tissue by tumor cells Angiogenesis Metastasis Development of secondary tumors
  • 10. Cancer cells differ from normal cells by • Uncontrolled proliferation • De-differentiation & loss of function • Invasiveness • Metastasis
  • 11. Guiding principles in cancer chemotherapy • To achieve cure a TOTAL CELL KILL must be tried • Early diagnosis and early institution of treatment • Combination chemotherapy • Intermittent regimens • Adjuvant and neoadjuvant chemotherapy occasionally
  • 12. Total cell kill • Aimed at destroying all the malignant cells, leaving none • This approach ensures – Early recovery – Prevents relapse – Prolongs survival • Pharmacological sancturies
  • 13. Effects of various T/t on cancer cell burden
  • 14. • Survival time inversely related to initial number of cells • Aging cancer cells are less susceptible to chemotherapy, because there is – ↑ cell cycle (division) time – ↓No of actively dividing cells with more resting cells – ↑ cell death within tumor – Overcrowding of cells
  • 15. Combination chemotherapy? • Heterogenicity of cells remaining in different phase of growth cycle , showing different level of sensitivity – Nature of drug (with different biochemical site of action) – Avoid emergence of drug resistance • Monotherapy adequate in Burkitts lymphoma & choriocarcinoma
  • 16. Why intermittent regimen? • Favours risk –benefit ratio • Allows time for damaged normal host cells to recover • Pulse therapy – Type of intermittent chemotherapeutic regime employing highest tolerated dose within a short administration period – Based on principle of drug conc. (C) x duration of exposure (T) = constant
  • 17. Adjuvant & Neoadjuvant chemotherapy • Adjuvant chemotherapy: – Chemotherapy given after surgery or irradiation to destroy micrometastasis & prevent development of secondary neoplasm. • Neo-adjuvant chemotherapy: – Chemotherapy given before surgery or radiotherapy in order to diminish the volume of large primary neoplasm
  • 18. • Nausea & Vomiting • Bone marrow depression • Alopecia • Gonads: Oligospermia, impotence, ↓ ovulation • Foetus: Abortion, foetal death, teratogenicity • Carcinogenicity • Hyperuricemia • Immunosupression: Fludarabine • Hazards to staff General toxicity of cytotoxic drugs
  • 19. Phases of cell cycle
  • 20. CLASSIFICATION - I: CELL CYCLE NON SPECIFIC : Kills resting cells & dividing cells • Cyclophosphamide • Chlorambucil • Cisplatin • Actinomycin-D • L-asparaginase CELL CYCLE SPECIFIC Kills actively dividing cells • G1 – Vinblastine • S – Methotrexate 6-Mercaptopurine 5-Fluorouracil • G2 –Bleomycin Etoposide, Topotecan Daunorubicin • M – Vincristine Vinblastine Paclitaxel,Docetaxel
  • 21. CLASSIFICATION - II: Depending on mechanism at cell level • Directly acting cytotoxic drugs: – Alkylating agents – Antimetabolites – Natural products • Antibiotics • Vinca alkaloids • Taxanes • Epipodophyllotoxins • Camptothecin analogs • Enzymes • Biological response modifiers – Miscellaneous: Cisplatin, carboplatin • Indirectly acting- by altering the hormonal mileau : – Corticosteroids – Estrogens & ERMs – 5 alpha reductase inhibitors – Gnrh agonists – Progestins
  • 22. • Nitrogen Mustards – Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide • Ethyleneimine : Thiotepa • Alkyl Sulfonate: Busulfan • Nitrosureas – Carmustine,lomustine, streptozocin • Triazines – Dacarbazine, temozolamide Alkylating agents
  • 23. • Folate Antagonists – Methotrexate • Purine Antagonists – 6 Mercaptopurine, 6 Thioguanine, Azathioprine • Pyrimidine antagonists – 5 Fluorouracil, cytarabine, gemcitabine Antimetabolites
  • 24. • Antibiotics – Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitomycin C • Vinca alkaloids – Vincristine, Vinblastine, Vinorelbine • Taxanes – Paclitaxel, docetaxel • Enzymes – L-Asparginase Natural Products • Epipodophyllotoxins – etoposide, tenoposide • Camptothecin analogs – Topotecan, irinotecan • Biological response modifiers – Interferons, – Interleukins
  • 25. • Cisplatin • Carboplatin • Hydroxurea • Procarbazine • Mitotane • Imatinib Miscellaneous Agents
  • 26. Hormones & antagonists • Corticosteroids – Prednisolone • Estrogens – Ethinyl Estradiol • SERM – Tamoxifene, Toremifene • SERD – Fulvestrant • Aromatase Inhibitors – Letrozole, Anastrazole, Exemestane • Progestins – Hydroxyprogesterone • Anti-androgens – Flutamide, Bicalutamide • 5- reductase Inhibitors – finasteride, dutasteride • GnRH analogs – Naferelin, goserelin, leuoprolide
  • 27. MOA of some anticancer drugs Purine & Pyrimidine synthesis Ribonucleotides Deoxy ribonucleotides DNA RNA Proteins Purine/ Pyrimidine antagonists Methotrexate Inhibition of purine ring & dTMP biosynthesis 5 FU inhibits dTMP synthesis Dactinomycin , Intercalate with DNA disrupt DNA function Alkylating agents Alter structure & function of DNA by cross linking and/or fragmenting DNA Cytarabine inhibits DNA chain elongation
  • 28. Alkylating agents • Nitrogen Mustards (MCI) – Meclorethamine, Melphalan, Chlorambucil, Cyclophosphamide, Ifosfamide • Ethyleneimine : Thiotepa • Alkyl Sulfonate: Busulfan • Nitrosureas – Carmustine,lomustine, streptozocin • Triazines – Dacarbazine, temozolamide
  • 29. Mechanism of action Alkylating Agents Form highly reactive carbonium ion Transfer alkyl groups to nucleophilic sites on DNA bases Results in Cross linkage Abnormal base pairing DNA strand breakage ↓ cell proliferation Alkylation also damages RNA and proteins
  • 31. • Cytotoxic action – Hemopoetic system highly susceptible • Chlorambucil – more against lymphoid series • Busulfan – more against myeloid series – Epithelial tissues, hair follicles – Spermatogenesis , fetopathic effect • Immunosupressant action • Miscellaneous – Severe nausea & vomiting • Known as radiomimetic drugs Pharmacological actions
  • 32. • Mechlorethamine • Melphalan • Chlorambucil • Cyclophosphamide • Ifosfamide Nitrogen Mustards
  • 33. • Very irritant drug • Dose = 0.4 mg/kg single or divided • Uses – Hematological cancers , lymphomas , solid tumors • Adverse effects – Anorexia, nausea, vomiting – Bone marrow depression, aplasia – Menstrual irregularities • Estramustine Mechlorethamine (Mustine)
  • 34. Melphalan • Very effective in MULTIPLE MYELOMA • Less irritant locally , less alopecia • Dose: 0.25 mg/kg daily for 4 days every 4-6 weeks • Adverse Effects : – Bone marrow Depression – Infections , diarrhoea and pancreatitis
  • 35. • Most commonly used alkylating agent a prodrug Cyclophosphamide
  • 37. Uses of cyclophosphamide • Neoplastic conditions – Hodgkins and non hodgkins lymphoma – ALL (Acute Lymphoblastic leukemia), CLL (Chronic Lymphocytic leukemia), Multiple myeloma – Burkits lymphoma – Neuroblastoma , retinoblastoma – Adenocarcinoma of ovaries • Non neoplastic conditions – Control of graft versus host reaction – Rheumatoid arthritis – Nephrotic syndrome
  • 38. • Adverse effects: – Hemorrhagic cystitis, – alopecia, – nausea & vomiting, – SIADH – hepatic damage • Dose: 2-3 mg/kg/day oral 10-15 mg/kg IV every 7-10 days • It can be administered IV, IM, IP, intrapleurally, Intraarterialy, directly into tumor Cyclophosphamide
  • 39. Ifosfamide • Congener of cyclophosphamide • Longer half life than cyclophosphamide • Less alopecia and less emetogenic than cyclophosphamide • Can cause hemorrhagic cystitis and severe neurological toxicity • Used for germ cell testicular tumors and adult sarcomas
  • 40. Chlorambucil (Leukeran) • Slowest acting and least toxic alkylating agent • Main action on lymphoid series produces marked lympholytic action • Drug of choice for long term maintenance therapy of CLL • Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance
  • 41. ThioTEPA • Triethylene phosphoramide • Does not require to form active intermediate • Active intravesicular agent can also be used topicaly in superficial bladder cancer • Not well absorbed orally given IV • High toxicity
  • 42. Busulfan (Myleran) • Depresses bone marrow with selective action on myeloid series • Primarily used in Chronic myelogenous leukemia 2-6 mg/day • Adverse effect: – Interstitial pulmonary fibrosis – Venoocclusive disease of liver – Hyperuricaemia – Sterility
  • 43. Nitrosureas • Highly lipid soluble, Cross BBB • Uses: – Meningeal / Brain tumours • Dose :150-200 mg/m2 BSA every 6 wks (Carmustine) • Adverse Effects: – Delayed bone marrow suppression – Visceral fibrosis, renal damage
  • 44. Triazenes • Dacarbazine – Primary inhibitory action on RNA & protein synthesis – Used in malignant melanoma • Temozolamide – New alkylating agent – Approved for malignant glioma – Rapidly absorbed after oral absorption & crosses BBB
  • 45. Mechanisms of resistance of alkylating agents • ↓ Influx of drug • ↑ Production of nucleophilic substances like glutathione that compete with target DNA for alkylation • ↑ Activity of DNA repair enzymes • ↑ metabolic inactivation of drugs
  • 46. Cisplatin • Non cell cycle specific killing • Administered IV • Highly bound to plasma proteins • Gets conc in kidney, intestine, testes • Poorly penetrates BBB • Slowly excreted in urine Pt NH3Cl Cl NH3 Dose: 20 mg/m2 for 5 days a week 75 – 100 mg/m2 once in 4 weeks to treat ovarian cancer
  • 47. Mechanism of action of cisplatin Cisplatin enters cells Forms highly reactive platinum complexes DNA damage Intra strand & interstrand cross links Inhibits cell proliferation
  • 48. Cisplatin uses and adverse effects • Uses – Testicular cancer (85% - 95 % curative ) – Ovarian cancer – Other solid tumors: lung, esophagus, gastric • Adverse effects – Emesis – Nephrotoxicity – Peripheral neuropathy – Ototoxicity
  • 49. Carboplatin • Better tolerated • Nephrotoxicity , ototoxicity , neurotoxicity low • Less emetogenic • But thrombocytopenia and leukopenia may occur • Less plasma protein binding • Use: – primarily in ovarian cancer of epithelial origin – Squamous cell carcinoma of head and neck
  • 50. Antimetabolites • Folate Antagonists – Methotrexate • Purine Antagonists – 6 Mercaptopurine, 6 Thioguanine, Azathioprine • Pyrimidine antagonists – 5 Fluorouracil, cytarabine, gemcitabine
  • 51. Methotrexate Adenine, guanine, thymidine , methionine, serine Folic acid not useful in toxicity Folinic acid N5 formyl FH4 should be given which is converted to N5,N10- Methylene –FH4 and bypasses the inhibited reductase
  • 52. Pharmacological actions • Cytotoxic actions – Predominant on bone marrow – Ulceration of intestinal mucosa – Crosses placenta interferes with embroyogenesis foetal malformations and death • Immunosupressive action – Prevents clonal expansion of B & T lymphocytes • Anti-Inflammatory action – Interferes with release of inflammatory cytokines IL-2, IL-6,IL-8 & TNF- , ↓ Rheumatoid Factor production
  • 53. Pharmacokinetics • Absorbed orally, 50 % protein bound • Disappears rapidly from blood , remains in tissue longer than folate thus causes prolonged inhibitory effect • C/I in renal impairment
  • 54. Adverse effects • Megaloblastic anemia • Thrombocytopenia, leukopenia, aplasia • Oral, intestinal ulcer , diarrhoea • Alopecia , liver damage, nephrpathy  Folinic acid (citrovorum factor, N5 Formyl THF)  IM/IV 8 to 24 hrs after initiation of methotrexate  120 mg in divided doses in first 24 hrs, then 25 mg oral/IM 6 hrly for next 48 hrs Treatment of methotrexate toxicity
  • 55. Uses of methotrexate • Antineoplastic – Choriocarcinoma and tropoblast tumor 15 -30 mg/day orally for 5 days – Remission of ALL in children 2.5 to 15 mg/day – Ca breast, head & neck, bladder, ovarian cancer • Immuno-supressive agent – Rheumatoid arthritis, resistant asthma – Crohns disease, wegeners granulomatosis – Prevention of graft versus host reaction • Psoriasis • Medical termination of pregnancy
  • 56. • 6 Mercaptopurine • 6 Thioguanine • Azathioprine • Fludarabine Purine antagonists
  • 57. 6 Mercaptopurine 6 MP 6 Thiouric acid Xanthine oxidase Allopurinol TPMT Inactive metabolite
  • 58. • Use: – Acute leukemia (ALL) – Choriocarcinoma • Adverse Effects: – Bone marrow & GIT mainly – Hepatic necrosis rarely – Hyperuricaemia 6 Mercaptopurine
  • 59. • Phosphorylates intracellularly to form triphosphate • Inhibits DNA polymerase and gets incorporated to form dysfunctional DNA • Effective in slow growing tumors: (apoptosis) • Use: – CLL and non hodgkins recurring after treatment • Adverse events: – chills, fever, opportunistic infection, myelosupression Fludarabine
  • 60. • Like fludarabine converted to triphosphate • Incorporated into DNA • Inhibits DNA polymerase  and  thus inhibits DNA synthesis and repair • Used in treatment of Hairy cell leukemia, CLL and low grade lymphomas Cladirabine
  • 61. Pentostatin Inhibits adenosine deaminase Accumulation of adenosine & deoxyadenosine Inhibits ribonucleotide reductase Blocks DNA synthesis S adenosyl homocysteine accumulation Toxic to lymphocytes Used in Hairy cell leukemia
  • 62. • 5 fluoruracil • Cytosine arabinoside (Cytarabine) • Gemcitabine Pyrimidine antagonists
  • 63. 5 fluorouracil 5 FU FdUMP dUMP Thymidine Monophosphate Thymidilate synthetase DNA Synthesis (Selective failure) Uses : stomach , colon, breast ovaries , liver, skin cancers FdUMP = fluorodeoxyuridine monophosphate
  • 64. • Pyrimidine analog considered drug of choice in inducing remission in AML • Phosphorylated in body to triphosphate • Triphosphate of cytarabine inhibits DNA polymerase  &  • Thus inhibit DNA synthesis and repair Cytosine arabinoside Gemcitabine • Drug of choice in adenocarcinoma of pancreas
  • 65. • Obtained from periwinkle plant ( Vinca Rosea) • Vincristine, vinblastine, vindesine, vinorelbine Vinca alkaloids
  • 67. Comparison between Vincristine • Marrow sparing effect • Alopecia more common • Peripheral & autonomic neuropathy & muscle weakness (CNS) • Constipation • Uses: (Childhood cancers) – ALL , Hodgkins, lymphosarcoma, Wilms tumor, Ewings sarcoma Vinblastine • Bone marrow supression • Less common • Less common, temp. mental depresssion • Nausea, vomiting, diarrhoea • uses – Hodgkins disease & other lymphomas , breast cancer, testicular cancer
  • 68. Taxanes • Paclitaxel & docetaxel • Plant product obtained from bark of Pacific Yew ( Taxus Brevifolia) & European Yew (Taxus Buccata)
  • 69. Mechanism of action Cell cycle arrested in G2 and M phase
  • 70. • Paclitaxel – Administered IV – Use: advanced breast & ovarian cancer also lungs, esophagus, prostrate cancer – Adverse effects: • Anaphylactoid reaction because of solvent cremaphor • Myalgia, myelosupression, peripheral neuropathy • Docetaxel – Oral – Used in refractory breast & ovarian cancer – Major toxicity neutropenia may cause aarrhythmias , hypotension
  • 71. Epipodophyllotoxins • Etoposide & tenoposide • Semisynthetic derivatives of podophyllotoxins podophyllum peltatum (plant glycoside)
  • 72. Etoposide • Act in S & G2 phase • Inhibit topoisomerase II which results in breakage of DNA strands & cell death • Uses: – Testicular tumors , squamous cell cancer of lungs
  • 73. • Derived from camptotheca accuminata • Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted • Topotecan: – Used in metastatic ovarian cancer – Major toxicity is bone marrow depression • Irinotecan – Used in metastatic cancer of colon/rectum – Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects Camptothecin analogs
  • 74. • Cell cycle non specific drugs • Derived from streptomyces species • MOA: – Intercalation in the DNA between adjoining nucleotide pairs – blocks DNA & RNA synthesis – Generation of oxygen radicals which mediate single strand scission of DNA – Action on Topoisomerase II Anticancer antibiotics
  • 75. • Uses: – Wilms tumor, – gestational choriocarcinoma • Adverse effects – bone marrow supression – Irritant like meclorethamine – sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur – Gastrointestinal adverse effects Dactinomycin
  • 77. • Doxorubicin: – Used in acute leukemias, malignant lymphoma and many solid tumors, direct instillation in bladder cancer • Daunorubicin: – Use limited to ALL and granulocytic leukemias • Toxicity: – Both cause cardiotoxicity (cardiomyopathy) – Marrow Depression, Alopecia
  • 78. • Mitoxantrone – Analog of doxorubicin – Lower cardiotoxicity – Uses: Acute leukemia, CML, Non hodgkins • Mitomycin C – Highly toxic used only in resistant cancers of stomach, colon, rectum – Transformed to form which acts like alkylating agent • Mithramycin – Reduces blood calcium levels by inhibiting osteoclasts – Used in T/t of hypercalcemia with bone metastasis
  • 79. Bleomycin Reacts with iron, copper & O2 in presence of CYP -450 reductase Also can intercalate between DNA strands DNA – bleomycin – Fe2+ DNA – bleomycin – Fe3+
  • 80. • Uses : – Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus – Testicular tumors – Hodgkins lymphoma • Adverse effects: – Pneumonitis – Fatal pulmonary fibrosis – Hyper pigmentation – spares bone marrow Bleomycin
  • 82. L-asparaginase • Isolated from E.coli • Use: Acute Lymphocytic Leukemia (ALL) • Dose : • 6000 to 10000U/kg IV daily for 3-4 weeks • A/E: • Hepatic damage • Hypersensitivity , hemorrhage • Hyperglycemia, headache, hallucinations , confusion, coma
  • 83. Hydroxyurea • Uses: • CML, Polycythemia, psoriasis • Dose: • 20-30 mg/kg /day orally Ribonucleotides Deoxyribonucleotides Ribonucleoside diphosphate reductase Hydroxyurea • Adverse effects • Myelosuppression (Minimal) • Hypersensitivity • Hyperglycemia • Hypoalbuminemia
  • 84. Procarbazine • MOA: Depolymerizes DNA & causes chromosomal damage • USES: Hodgkin’s disease ( MOPP regimen) • Non hodgkins lymphoma • 100-200mg daily orally • A/e: MAO inhibitor action & antabuse action
  • 85. Radio active isotopes • I131 – Emits beta radiation , half life-8.04 days use:Follicular Ca- Thyroid • P32 - Emits beta radiation , half life- 14.3 days. use : Polycythemia vera • 198Au – gives low energy beta & gamma radiation, half life- 2.69 days use :malignant pleural, peritoneal effusion
  • 86. Hormones & antagonists • Corticosteroids – Prednisolone • Estrogens – Ethinyl Estradiol • SERM – Tamoxifene, Toremifene • SERD – Fulvestrant • Aromatase Inhibitors – Letrozole, Anastrazole, Exemestane • Progestins – Hydroxyprogesterone • Anti-androgens – Flutamide, Bicalutamide • 5- reductase Inhibitors – finasteride, dutasteride • GnRH analogs – Naferelin, goserelin, leuoprolide
  • 87. Glucocorticoids • Marked lympholytic effect so used in acute leukaemias & lymphomas, • They also – Have Anti-inflammatory effect – Increase appetite, prevent anemia – Produce sense of well being – Increase body weight – Supress hypersensitivity reaction – Control hypercalcemia & bleeding – Non specific antipyretic effect – Increase antiemetic effect of ondansetron
  • 88. Estrogens • Physiological antagonists of androgens • Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer • Fofesterol – Prodrug , phosphate derivative of stilbesterol – 600-1200mg IV initially later 120-240 mg orally
  • 89. • Tamoxifen : Non steroidal antiestrogen Selective Estrogen Receptor Modulators (SERMs) Agonistic: Uterus, bone, liver, pitutary Antagonistic: Breast and blood vessels
  • 90. Tamoxifen • DOSE:10-20mg bd • Standard hormonal treatment in breast cancer • Adverse effects: – Hot flushes , vomiting, vaginal bleeding, menstrual irregularities, venous thromboembolism, dermatitis, rarely endometrial cancer
  • 91. • Pure estrogen antagonist • USES: Metastatic ER+ Breast Ca in postmenopausal women • MOA: • Inhibits ER dimerization & prevents interaction of ER with DNA • ER is down regulated resulting in more complete supression of ER responsive gene function Selective Estrogen Receptor Down regulator (fulvestrant)
  • 92. • Letrozole • Orally active non steroidal compound • MOA : Inhibits aromatisation of testosterone & androstenedione to form estrogen. • Uses : Breast Ca- & adj. to mastectomy • Dose :2.5mg bd orally • Anastrozole : more potent • 1mg OD in ER+ Breast Ca • A/E : hot flushes Aromatase Inhibitors
  • 93. • FLUTAMIDE & BICALUTAMIDE : • Androgen Receptor antagonists • Dose : 250 mg tds, 50mg od resp. • Palliative effect in metastatic Prostatic Ca after orchidectomy Anti androgens
  • 94. 5- reductase inhibitors Finasteride • Orally active • DHT levels ↓ • Benign prostatic hyperplasia Dose: 5mg/day Prostate volume Symptom score Peak urine flow rate DHT level in prostate Side effects: Loss of libido & impotence in 5 % pts. Also used for prevention of hair loss
  • 95. • NAFERELIN : nasal spray / SC inj • ↓FSH & LH release from pituitary- ↓ the release of estrogen & testosterone • USE : Breast Ca, Prostatic Ca • PROGESTINS: • Hydroxyprogesterone – used in metastatic endometrial Ca. • A/E: bleeding GnRH agonists
  • 98. Newer anticancer drugs • Inhibitors of growth factors receptors – Imatinib: CML (BCR-ABL gene) – Gefitinib: Non small cell cancer of lungs (EGFR) – Nilotinib : CML (Tyrosine kinase inhibitor) – Dasatinib : CML (Tyrosine kinase inhibitor) – Lapatinib : metastatic breast cancer (HER2/neu) – Sunitinib : renal cell carcinoma (VEGF) – Sorafinib : renal cell carcinoma (VEGF)
  • 99. • Monoclonal antibodies – Trastuzumab : breast cancer (HER2/neu) – Bevacizumab: metastatic colon cancer (VEGF) – Rituximab : non hodgkins lymphoma (CD-20) – Panitumumab : metastatic colon cancer (EGFR) – Alemtuzumab : CLL (CD 52 antigen) – Iodine tositumonab : Non hodgkins (CD-20) Newer anticancer drugs
  • 101. Important drug combinations REGIMEN CANCER DRUGS MOPP Hodgkins Mechlorethamine, oncovin, prednisolone, procarbazine ABVD Hodgkins Doxorubicin, bleomycin, vinblastine, dacarbazine CMF Breast Cyclophosphamide, methotrexate, 5-FU CAF Breast Cyclophosphamide, doxorubicin, 5FU ALL Vincristine, prednisolone, aspargine, daunorubicin AML Cytarabine, methotrexate CML Hydroxyurea, interferon Wilms Actinomycin, vincristine, doxorubicin

Editor's Notes

  1. Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of bodys own cells. It is one of the major causes of death in developed nations atleast 1 in 5 of the population of europe and north america can expect to die of cancer. Cancers are more common in aged people as life expectancy is increasing the incidence of cancers is also increasing, with the present methods of treatment one third of the patients are cured with local modalities of treatment (surgery or irradiation therapy) which are quite effective when the tumor has not metastatized. In metastasis systemic chemotherpy is required along with surgery or irradiation at present 50 % of the patients of cancer can be treated with chemotherapy contributing to cure in 10 -15% of the patients. The terms cancer,malignant neoplasm and malignant tumor are synonymous
  2. Hence target selectivity is more difficult in cancer*(exception in lymphoma , there is substantial selectivity)
  3. Chemotherapy is essentially required with surgery or irradiation when metastasis has occurred
  4. Shrinkage of tumor , alleviation of symptoms
  5. Other factors – promoters cocarcinogen, hormones, -- likely hood of mutation
  6. Aimed at destroying all the malignant cells, leaving none (lack of participation of host defence/immune response)order kinetics i.e given dose of a drug destroys constant fraction of cells. Term log kill is used to describe this phenomenon e.g leukemia diagnosis made when load of cells is >109 consequently if t/t leads leads to kill 99.99% of the cells then 0.001% i.e 104 cells remain this is equivalent to 5 log kill i.e 100000 fold. At this point patient appears asymptomatic i.e patient is in remission. For most bacterial infections a 5 log fold reduction in no of micro-organisms leads to cure . Since immune system can eradicate remaining bacterial cells. However cancer cells are not so easily destroyed Pharmacological sancturies: leukemia or other tumor cells find sanctury in tissues like CNS in which some chemotherapeutic agents can not enter, because of its transport constraints so pt may require irradiation of cerebrospinal axis or intrathecal administration of drugs at that site Cells of solid tumors can be considered as belonging to 3 compartments Compartment A: Consists of dividing cells, possibly being continously in cell cycle Compartment B: consists of resting cell in Go phase , the cells though not dividing are potentially able to do so Compartment C: cells no longer able to divide but contribute to tumor volume Essentially only cells in compartment A which may form as little as 5 % of some solid tumors are currently susceptible to main available cytotoxic drugs. Log kill: destruction of cancer cells by chemotherapeutic agents follows first
  7. Overcrowding of cells: poor blood supply and nutrition and defective access of drugs
  8. Heterogenecity of cells –
  9. Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells
  10. Sulfur mustard in 1917 was first used alkylating agent in WW-1, it was used as chemical warfare and caused severe skin vesication, vesication in mucous membrane , GI ulcerations and myelosupression. The pharmacological actions became evident only after world war 2.
  11. All alkylating agents have alkyl groups and they can transfer this alkyl group to suitable receptor site. Alkylating agents in neutral or alkaline solution form highly reactive carbonium ion which is quaternary ammonium derivative(The carbon atom has only six electrons in its outer space so highly reactive). This carbonium ion is highly reactive and can react with groups like NH2, SH, OH or PO4 in physiologically important molecules in cell and render them unavailable for normal metabolic reactions. One more property of this carbonium ion is its nucleophilicity it can react with nucleic acid bases and inhibit DNA synthesis . The nitogen at guanine position 7 is especially more susceptible. So this results in cross linking inhibits DNA replication . Abnormal base pairing (alkylated guanine pairs with thymine instead of cytosine) results in production of defective protein DNA strands breakage – decreased cell proliferation Alkylation also damages RNA and proteins Non cycle specific
  12. Alkylation of guanine bases in DNA MOA OF MECHLORETHAMINE
  13. Common to the alkylating agents Cytotoxic action in general damage nuclei of growing multiplying cells, hemopoetic system highly susceptible to this action leads to anemia, thrombocytopenia, leukopenia and in toxic doses bonemarrow supression., Net result similar mode of action may differ chlorambucil more effective against lymphoid series and busulfan more effective against myeloid series. These drugs also effect epithelial tissues like cornea, intestinal mucosa leading to desquamation and ulcers Hair follicles- alopecia’sprematogenesis, foetopathy sand ammenorrhoea Immunosupressant action : supress antibody production Miscellaneous: nausea, vomiting Radiomimetic drugs: actions resemble that of biological or ionizing radiations, all alkylating agents different radiomimetic action.
  14. First nitrogen mustard to be used in cancer chemotherapy Very irritant drug: vesicant for skin, eyes, resp tract , should be given only IV , Special care sloughing can occur with extravasation Available as 10 mg HCL with 90 mg NACL should be reconstituted in 10 ml NS or distilled water and given immediately because it becomes active in few minutes Hodkins stage III and stage IV as a part of MOPP mechlor, oncovin (Vincristine), procarbazine, prednisolone Chronic myelogenous leukemia, chronic lymphoblastic leulemia Because of serious toxicity use replaced by less toxic drugs carmustine Estramustine: stable combination of estrogen & mustine designed to deliver mustine to estrogen receptor site of tumor like prostrate cancer Advantage: both cytostatic and hormonal effect
  15. Also used in advanced ovarian tumor, otherwise toxic effects and properties similar to mechlorethamine
  16. Pharmacological actions similar to mechlorethamine Prodrug converted in body to active
  17. Hemorrhagic cystitis is specific toxicity of cyclophosphamide it is associated with dysuria, hematuria due to irritation of bladder mucosa by acrolein it is dose limiting toxicity. Mesna is also excreted in urine where it binds to and inactivates acrolein Should be given simultaneously and also 4-8 hrs after Acetyl cysteine can also be given Adequate hydration IV mesna (2 mercapto ethane sulfonate )
  18. Wegeners granulomatosis
  19. Less damaging to the platelets can also cause transverse ridging of nails, increased pigmentation Leucocyte count serves as guide to dosage adjustment in prolonged therapy neutrophil count = 500 to 1000cells /mm3 desired target
  20. 1g vial+3 mesna ampoules 200mg for IV Bronchogenic, Breast, Testicular, Bladder , Head & Neck Carcinomas, Osteogenic Sarcoma& some lymphomas
  21. Also used in hodkins and other solid tumors
  22. Unique in that in conventional doses of busulfan exert few pharmacological actions other than myelosupression Other use- polycythemia vera Pigmentation of skin
  23. Streptozocin indicated for T/t of islet cell carcinoma of pancreas 500mg/m2 for 5 days or 1000 mg/m2 weekly
  24. Acquired resistance to one alkylating agent often but not always imparts cross resistance to others Guanine –o-alkyl transferase
  25. Heavy metal complex has water soluble planar coordination complex containing central platinium atom surrounded by 2 cl and 2 nh3
  26. Nephrotoxicity can be reduced by hydration of patients and diuresis by litres of normal saline and mannitol, Hyperuricaemia can occur Neuropathy : large sensory fibres – numbness, tinglingfollowed by loss of joint position and disabling sensory ataxia Ototoxicity : tinnitus and hearing loss in high frequency range , more pronounce in children Rarely shock mutagenic, teratogenic , carcinogenic adverse events reversible on stoppage
  27. Excreted by kidneys t1/2 4to 6 hrs Oxaliplatin : less myelosupression but more paresthesia
  28. Chemical substance which takes part in cellular metabolic reactions is called metabolite Antimetabolite is a chemical substance which by virtue of its close structural resemblence to metabolite blocks its action it can achieve this by 2 methods By preventing the combination of metabolite with its specific enzyme By itself combining with specific enzyme and getting converted to either metabolically inactive or harmful to cell ( lethal synthesis)
  29. One of most commonly used anticancer agents Cell cycle specific drug acts in S phase Methotrexate has antineoplastic, immunosuoressant and anti-inflammatory action It produced the first striking although temporary remission of leukemia and first cure for choriocarcinoma Mechanism of action of methotrexate: methotrexate structurally resembles folic acid , it competitively inhibits dihydrofolate reductase enzyme and blocks conversion of DHFA to THFA THFA is an essential coenzyme required for one carbon transfer reactions in denovo purine synthesis and synthesis of thymidilate , amino acid conversions which are required for DNA SYNTHESIS it also inhibits RNA and protein synthesis. More toxic to rapidly dividing cells likw bone marrow
  30. Inhibit erythropoeisis, myelopoesis, and finally aplasia --- marked granulocytopenia , reticulocytopenia
  31. Calcium folinate or calcium levofolinate Thymidine also counteracts methotrexate toxicity
  32. Choriocarcinoma and tropoblast tumor in women xure RHEUMATOID ARTHRITIS :5-7.5MG PER WEEK ORALLY FOR 8 WEEKS PSORIASIS 2.5-5MG AT 12HRLY INTERVALS WEEKLY Also used in mycosis fungoides , Some role in AML and non hodgkins lymphoma MTP: 25 TO 50 MG ORAL THEN 3-7 DAYS LATER misoprostol 800 microgram vaginally in early part of forst trimester < 8 weeks of gestation
  33. Well absorbed orally, metabolized rapidly by xanthine oxidase, use of xanthine oxidase inhibitor allopurinol decreases the inactivation of 6 MP, xanthine oxidase also required in uric acid synthesis, so allopurinol may be used in cancer chemotherapy to reduce dose of 6 MP and also decrease the hyperuricaemia 6 MP ALSO METABOLISED BY METHYLATION IN PRESENCE OF ENZYME THIOPURINE METHYL TRANSFERASE, GENTIC DEFICIENCY OF THIS ENZYME MAKES INDIVIDUAL MORE SUSCEPTIBLE TO 6 MP toxicity , while over expression is important method of resistance. Azathiprine is also substrate for xanthine oxidase but 6 thiguanine is not.
  34. Hyperuricaemia occurs due to massive destruction of cells of lymphoid series , urine should be maintained alkaline and its volume adequate. Other purine analogs like 6 thioguanine and azathiprine also posses cytotoxic actions how ever they do not have any advantage over 6 mercaptopurine as antileukemic agents Mercaptopurine with azathiprine decrease the dose by ¼ to ½ Azathiprine: Imuran Used as immunosupressive agent in organ transplantation and autoimmune conditons like hemolytic anemia, glomerulonephritis, and rhe umatoid arthritis
  35. Promotes tumor apoptosis
  36. Extremely effective in complete remission of hairy cell leukemia iv 4 g/m2 alternate week , sufficient hydration 500 ml to 1 l of dextrose in 0.45 % saline
  37. 5 fluoro uracil is converted in body to corresponding nucleotide fluorodeoxyuridine monophosphate, Fluorinated analog of pyrimidine acts by inhibiting thymidilate synthesis Also gets incorporated into DNA in place of uracil Uses: topically intreatment of premalignant keratosis Even resting cells are more affected though rapidly multipling cells are more susceptible Toxic to bone marrow , alimentary epitheliumand CNS Administered by slow IV infusion to prevent first pass metabolism.
  38. ESPECIALLY IN ADULTS Uses : AML, Hodgkins & Non hodgkins Gemcitabine Forms triphosphate that inhibits DNA synthesis Blocks DNA strand elongation Drug of choice in adenocarcinoma of pancreas 1000 mg/m2 over 30 min
  39. VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation Resistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.
  40. AFE: Unpredictable oral absorption, extensively conc in platelets, vinca alkaloids are not well absorbed by oral route Highly irritant drugs so given continously by iv infusion, vinca alkaloids are conc and metabolized by CYP450 in liuver excreted in bile in liver dysfunction decrease the dose Phenytoin, phenobarbitone, carbamezepine may induce the metabolism and griseofulvin inhibits metabolism Vinorelbine: semisynthetic derivative for ca breast, testicular cancer, epithelial ovarian cancers.
  41. Taxanes bind to beta tubulin subunits of microtubules at a site different from binding site of vinca alkaloids, colchicine, podophyllotoxin, unlike vinca alkaloids they promote polymerization of microtubules & inhibit depolymerization, leading to stabilization of polymerized microtubules and arrests cells in mitosis and eventually leads to activation of apoptosis The stabilization of microtubules is damaging to cells because of disturbances in in the dynamics of various microtubule dependent structures that are required for functions like mitosis, maintainence of cellular morphology, locomotion and secretion.
  42. Dexamethasone, h1 antagonists supress the reaction Abraxane: Albumin bound form of paclitaxel no anaphylactoid reaction
  43. Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Type II topoisomerase cuts both strands of one DNA double helix, passes another unbroken DNA helix through it, and then reanneals the cut strand. Testicular tumors in combination with bleomycin or cisplatin Tenoposide used in ALL
  44. Topoisomerase I modulates supercoiling of DNA by complexing with it and nicking one of its strands
  45. Intercalation in the DNA: The drugs insert nonspecifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis. Intercalation can interfere with the topoisomerase II–catalyzed breakage/reunion reaction of supercoiled DNA strands, causing irreparable breaks. Generation of oxygen radicals: Cytochrome P450 reductase (present in cell nuclear membranes) catalyzes reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA (Figure 39.18). Tissues with ample superoxide dismutase or glutathione peroxidase activity are protected.10 Tumors and heart tissue are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.
  46. Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA,8 forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals. Adverse effects: The major dose-limiting toxicity is bone marrow depression. The drug is immunosuppressive. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur.
  47. Acute: ecg changes, arrhythmia, hypotension, delayed CCF Tissues with ample superoxide dismutase or glutathione peroxidase activity are protected.10 Tumors and heart tissue are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.
  48. Mixture of closely related glycopeptide antibiotics
  49. CLINICAL RESPONSE TO L-ASPARGINASE IS DISAPPOINTING, THOUGH REMISSIONINDUCED IN ACUTE LEUKEMIA IS SHORT LASTING , IT IS NOW USED WHWN OTHER DRUGS HAVE FAILED , INEFFECTIVE IN SOLID TUMORS
  50. Blocks enzyme Less GI toxicity
  51. Methyl hydrazine derivative, inactive as such but undergoes metabolic activation to highly reactive alkylating species which cause methylation of DNA
  52. Emit b and gamma radiations disrupt cellular metabolism and cause cellular destruction.
  53. Prevent anemia: prevent acceletated erythrocytic destruction, They effectively counter hemolytic and hemorrhagic complications accompanying chronic lymphocytic and malignant lymphomas, Prednisolone is generally started in doses of 60 – 100 mg daily in divided doses and then depending on response reduced to maintenance dose of 20 -40 mg /day The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and decreased lymphoid mass. [Note: At high doses, cortisol is also lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes.] Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas. Glucocorticoids have some secondary role in hormone responsive breast cancers, they are also valuable for treatment of complications like treatment of hypercalcemia, hemolytic anemias, thrombocytopenia, incresed intracranial tension, mediastinal edema occuring after radiotherapy, they afford symptomatic relief by mood elevating and antipyretic effects and also adjuvants of antiemetics. Useful in treating cerebral edemas due to intracranial cerebral metastasis
  54. Fosfesterol is activated to slibesterol in prostatic tissue and acheives high conc in prostatic tissue thus it is used in prostrate cancer Adverse effects – impotence and gynaecomastia
  55. SERMS are non steroidal synthetic agents whose agonist or antagonist action on estrogen receptors are tissue selective, produces beneficial estrogenic actions in some tissues (bone, brain, liver), and prevent certain deleterious effect in breast and endometrium by exhibiting antagonistic or no action on ER Tamoxifen: Non steroidal antiestrogen related structuraly to slilbesterol, given orally it competes with the circulating estrogen for cytoplasmic estrogen receptor binding site, the metabolites of tamoxifen have much stronger affinity for receptors and are not easily displaced by circulating estradiol. At low concentration they have cytostatic effect on ER positive cells, higher conc cause cytotoxic effect . Because of antagonistic action in breast DOC in treatment of ca breast in ER+ AS WELL as some ER- breast cancer also male breast
  56. Well absorbed orally, biphasic half life 10 hrs and also 7 days, and long duration ofaction some metabolites of tamoxifen are more potent antiestrogens, the drug is excreted primarily in bile. Other SERMS- raloxifene – no risk of endometrial carcinoma, used as first line drug in treatment of postmenopausal osteoporosis, toremifene – new congener of tamoxifen with similar actions uses and adverse effects ORMELOXIFENE – dub, acts as antagonist in breast and uterus
  57. USES: Metastatic ER+ Breast Ca in postmenopausal women which has stopped responding to tamoxifen Higher affinity for ER probably accounts for efficacy in tamoxifen resistant cases
  58. Aromatization of A ring of testesterone and androstenedione is final and key step in production of estrogens estradiol and estrone in body, in addition to circulating hormone the locally produced hormone may play an important role in breast cancer development, exemestane also aromatase inhibitor