2. Cancer
Definition = Uncontrolled division of cells leading
to a tumour formation
• Local spread of cancerous tissue cause damage to
surrounding blood vessels, nerves, & nearby organs
• Can spread to distant organs by blood & lymphatics
=====Metastasis
• Cancer, malignant neoplasm & malignant tumour =
synonymous (metastasize)
• Benign tumour=Non invasive, unable to metastasize
3.
4. Causes of Cancer
• Exposure to ionizing radiation = causing acute
leukemias, thyroid cancer, breast cancer, lung cancer &
others
• Viruses ‐‐‐expression of viruses induced neoplasm
• Genetic mutation‐‐‐‐
i) Inactivation of tumour suppression genes
ii) Activation of proto‐oncogenes to oncogenes
6. Anticancer Drugs
• Either kill cancer cells or modify their growth
• Selectivity of majority of drugs is limited.
• They are one of the most toxic drugs used in therapy
• The latest innovations target growth factors, specific
signaling pathways, angiogenesis, tumour antigens,
immune therapies, etc. to introduce a different
spectrum of drugs.
• In addition to their prominent role in leukaemias and
lymphomas, drugs are used in conjunction with surgery,
radiotherapy and immunotherapy in the combined
modality approach for many solid tumors, especially
metastatic
7. • In malignant diseases, drugs are used with the aim
of
1. Cure or prolonged remissionPrimary
treatment modality
2. PalliationShrinkage of tumour, alleviation
of symptoms and life is prolonged
3. Adjuvant chemotherapyDrugs are used to
mop up any residual malignant cells after
surgery or radiotherapy
8. General toxicity of cytotoxic drugs
• Majority of the cytotoxic drugs have more effect on
rapidly multiplying cells
1. Bone marrowDepression of bone marrow
results in granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic anemia
2. Lymphoreticular tissueLymphocytopenia and
inhibition of lymphocyte function results in
suppression of cell mediated as well as humoral
immunity
9. 3.GITStomatitis, diarrhoea, shedding of mucosa,
haemorrhages, nausea and vomiting
4.Skin Alopecia occurs due to damage to the cells in
hair follicles. Dermatitis is another complication
5.GonadsInhibition of gonadal cells causes
oligozoospermia and impotence in males; inhibition of
ovulation and amenorrhoea are common in females
6.Foetus Cytotoxic drugs given to pregnant women
damage the developing fetus → abortion, fetal death,
teratogenesis
10. 7.Carcinogenicity Leukemias, lymphomas and
histiocytic tumors appear with greater frequency many
years after the use of cytotoxic drugs
8.Hyperuricemia This is secondary to massive cell
destruction (uric acid is a product of purine
metabolism). Gout and urate stones in the urinary tract
may develop.
• In addition to these general toxicities, individual
drugs may produce specific adverse effects
1. Vincristine causes neuropathy
2. Doxorubicin causes cardiomyopathy
3. Cyclophosphamide produces alopecia and cystitis
11. Oral complications of cancer
chemotherapy
• Oral mucosa is susceptible to cytotoxic drugs
because of high epithelial cell turnover
• Many chemotherapeutic drugs produce oral lesions
• Oral mucositis Early manifestation of toxicity. The
gingival tissue and oral mucosa are regularly
subjected to minor trauma during chewing and
breaches are common
• Oral microbial flora is large and can be the source of
local (e.g. periodontal abscess) as well as bloodborne
infection
12. • Neutropenia and depression of immunity caused by
the cytotoxic drug indirectly ↑ oral inf. chance
• Thrombocytopenia due to bone marrow depression
may cause gingival or mucosal bleeding
• Chemotherapeutic drugs frequently produce
Xerostomia (which accelerates development of
dental caries) angular cheilitis
• Dysgeuesia ( altered taste)
• Administered to children during tooth development,
cancer chemotherapy may cause hypoplasia of tooth,
blunting of roots and even tooth agenesis
13. Prevention of oral/dental complications
1. Thorough dental checkup before starting the
regimen
2. Any carious cavities, periodontal lesions, impacted last
molars and other potential sources of infection should
be appropriately treated
3. All sharp cusps or dentures should be smoothened to
avoid injury
4. Good oral hygiene should be maintained
throughout the course
5. Topical use of fluoride can retard caries
development
14. 6.Stomatitis and oral ulcers can be treated with
chlorhexidine mouthwash
7.Nystatin or Clotrimazole lotion may be used for
Candida infection
8.As mucositis progresses, oral lesions become
increasingly painful and may interfere with eating.
Topical application of sucralfate and misoprostol may
afford some relief
9.Benzocaine lozenges or lidocaine gel can reduce pain but
may interfere with taste and increase the risk of injury to
oral mucosa. Opioid analgesics may have to be prescribed
15. 10.Systemic antibiotics to cover organisms like
Pseudomonas, Klebsiella, E.coli are often needed in
addition to those for common oral pathogens (GPC &
anaerobes) when chemotherapy related oral inf. develop
11.In a patient receiving chemotherapy, any dental
procedure should be undertaken only after giving due
regard to his/her immune and haemostatic status and in
consultation with the patient’s physician
12.Appropriate prophylactic antibiotic to eliminate the
risk of infection is important, since infections can easily
set in or get disseminated in subjects compromised by
the chemotherapy
20. Alkylating agents
• Produce highly reactive carbonium ion intermediates
which transfer alkyl groups to cellular
macromolecules by forming covalent bonds
• Have cytotoxic and radiomimetic (like ionizing
radiation) actions
• Many are cell cycle nonspecific, i.e. act on dividing as
well as resting cells
• Cyclophosphamide M/c used, effective in a wide
range of tumors & has prominent immunosupp. acn.
21.
22. Other alkylating agents
1. Chlorambucil Selective for lymphoid tissue and is
used for maintenance therapy in chronic
lymphocytic leukaemia and Hodgkin’s disease
2. Busulfan Selective for myeloid elements and DOC
for chronic myeloid leukaemia
3. Melphalan Effective in multiple myeloma
4. Lomustine Highly lipid soluble (brain tumors and
meningeal leukemia)
5. Dacarbazine Used in malignant melanoma
6. Procarbazine Component of the MOPP regimen
for Hodgkin’s and related lymphomas
25. Platinum coordination complexes
Cisplatin Has alkylating and radiomimetic properties
1. Used for many solid tumours including lung,
bladder, esophagaus, stomach, head and neck as
well as metastatic testicular and ovarian carcinoma
2. Needs to be infused i.v.
3. Highly emetogenic
4. Strong antiemetic pretreatment is required
• Carboplatin Less reactive 2nd gen. platinum
complex that is better tolerated
• Oxaliplatin 3rd gen. complex which is active against
many tumors that have developed resistance to Cisplatin
27. Antimetabolites
• Analogues related to the normal components of DNA
or of coenzymes involved in nucleic acid synthesis
• Competitively inhibit utilization of normal substrate
or get themselves incorporated forming
dysfunctional macromolecules
• Folate antagonist Methotrexate
28. Methotrexate
• Inhibits dihydrofolate reductase (DHFRase)—
blocking the conversion of dihydrofolic acid (DHFA)
to tetrahydrofolic acid (THFA) which is an essential
coenzyme required for one carbon transfer reactions
in de novo purine synthesis and amino acid
interconversions
• Methotrexate primarily inhibits DNA synthesis, but
also affects RNA and protein synthesis
• It exerts major toxicity on bone marrow
31. • Aspirin and sulfonamides ↓ its renal tubular
secretion ↑ toxicity
• The toxicity of Mtx cannot be overcome by folic
acid, because it will not be converted to the active
coenzyme form
• However, Folinic acid (N5 formyl THFA,
cirtrovorum factor) rapidly reverses the effects
• High dose Mtx with ‘folinic acid rescue’ has
been employed in many difficult to treat
neoplasms
32. Uses of Methotrexate
• Inhibit – Immunosuppressant
• C – Crohn’s disease
• A – Abortion
• N – Non Hodgkin Lymphoma
• C – Choriocarcinoma
• E – Ectopic pregnancy
• R – Rheumatoid arthritis
33. • Pemetrexed This is a new congener of methotrexate
that has found use in mesoepithelioma and nonsmall
cell lung cancer
34. Purine antagonists
• Mercaptopurine (6-MP) and thioguanine (6-TG) are
converted in the body to the corresponding
monoribonucleotides which inhibit purine synthesis
and utilization of purine nucleotides
• They are specially useful in childhood acute
leukaemia, choriocarcinoma and in some solid
tumours
35. • Azathioprine has marked effect on T lymphocytes,
suppresses cell mediated immunity (CMI) and is used
primarily as immunosuppressant in organ
transplantation, rheumatoid arthritis, etc.
• Azathioprine and 6MP are metabolized by xanthine
oxidase; their metabolism is inhibited by allopurinol;
dose has to be reduced to ¼–½ if allopurinol is given
concurrently.
36.
37. • Thioguanine is not a substrate for xanthine oxidase;
its dose need not be reduced if allopurinol is given
• Fludarabine is a newer antipurine that is active even
in some slow growing and recurrent cancers
• Toxicity
1. Bone marrow depression
2. Mucositis
3. Jaundice
4. Hyperuricaemia
38.
39. Pyrimidine antagonists
• Fluorouracil (5-FU) is converted in the body to the
corresponding nucleotide which blocks the
conversion of deoxyuridilic acid to
deoxythymidylic acid Selective failure of DNA
synthesis occurs
• Concurrent i.v. infusion of leucovorin (folinic
acid) enhances efficacy of 5FU
• Cisplatin is also synergistic
• Most treatment protocols for 5FU employ it
alongwith Leucovorin and Cisplatin
40.
41. • 5FU has been particularly used for many solid
tumours—breast, colon, urinary bladder, liver, head
and neck, etc.
• Capecitabine is an orally active prodrug of F.U.,
which is especially active against colorectal and
breast cancers
• Cytarabine is phosphorylated in the body to the
corresponding nucleotide which inhibits DNA
synthesis by DNA polymerase
• Uses Acute leukaemia in children & adults,
Hodgkin’s disease and non Hodgkin lymphoma
42.
43.
44. Microtubule damaging agents
• Vinca alkaloidsMitotic inhibitors, bind to
microtubular protein—‘tubulin’, prevent its
polymerization and assembly of microtubules, cause
disruption of mitotic spindle and interfere with
cytoskeletal function
• Chromosomes fail to move apart during mitosis:
metaphase arrest occurs
• Cell cycle specific & act in the mitotic phase
45. • Vincristine (oncovin) Childhood acute leukemia,
lymphosarcoma, Hodgkin’s disease, Wilms’ tumour,
Ewing’s sarcoma and carcinoma lung
• A/E Peripheral neuropathy and alopecia. Bone
marrow depression is minimal
• Vinblastine Employed with other drugs in
Hodgkin’s disease and testicular carcinoma
• Bone marrow depression is more prominent, while
neurotoxicity and alopecia are less marked than with
Vincristine
• VinorelbineSemisynthetic Vinblastine analogue
which is primarily used in non small cell lung
cancer
46.
47.
48.
49.
50. Taxanes
• Paclitaxel binds to β tubulin and enhances its
polymerization Inhibition of normal dynamic
reorganization of the microtubule network that is
essential for interphase and mitotic functions
• The indications of paclitaxel are metastatic ovarian
and breast carcinoma after failure of first line
chemotherapy. It has also shown efficacy in
advanced cases of head and neck cancer, small cell
lung cancer, esophageal adenocarcinoma, etc.
• Toxicity Reversible myelosuppression and
‘stocking and glove’ neuropathy
54. • Docetaxel More potent congener
• Indications
1. Breast & ovarian cancer refractory to 1st line drugs
2. Small cell cancer lung
3. Pancreatic carcinoma
4. Gastric carcinoma
5. Head/neck carcinoma
• Toxicity Neutropenia, but neuropathy is less
frequent
55. Estramustine
• Complex of estradiol with a nitrogen mustard has
weak estrogenic, but no alkylating property
• Binds to β tubulin preventing its organization into
microtubules (exerts antimitotic action)
• Indication Advanced or metastatic prostate cancer
56. Topoisomerase-2 inhibitor
• Etoposide arrests cells in the G2 phase and causes
DNA breaks by affecting DNA topoisomerase 2
function
• Uses
1. Testicular tumors
2. Lung cancer
3. Hodgkin’s and other lymphomas
4. Carcinoma bladder
57. Topoisomerase-1 inhibitors
• Topotecan & Irinotecan act in a manner similar to
Etoposide but interact with a different enzyme DNA
topoisomerase 1
• Uses Metastatic carcinoma of ovary and small cell
lung cancer after primary chemotherapy has failed
• Toxicity Bone marrow depression, especially
neutropenia
• Irinotecan Metastatic/advanced colorectal
carcinoma, cancer lung/cervix/ovary, etc.
• Dose limiting toxicity Diarrhoea
58.
59. Antibiotics
• Products obtained from microorganisms and have
prominent antitumour activity
• Intercalate b/w DNA strands & interfere with its
template function
• Actinomycin D (Dactinomycin) is highly efficacious
in Wilms’ tumour, rhabdomyosarcoma and a few
other malignancies
• A/E Vomiting, stomatitis, diarrhoea,
desquamation of skin, alopecia and bone marrow
depression
60. • Daunorubicin (Rubidomycin) Acute leukaemia
• Doxorubicin Acute leukaemia & solid tumours
• Dauno & Doxo are capable of causing breaks in DNA
strands by activating topoisomerase 2 and generating
quinone type free radicals
• ToxicityCardiotoxic (arrhythmias, cardiomyopathy,
heart failure; marrow depression, alopecia, stomatitis
62. • Bleomycin Chelates copper or iron, produces
superoxide ions and intercalates between DNA
strands—causes chain scission and inhibits repair
• Uses Testicular tumour, Squamous cell carcinoma
of skin, oral cavity, head and neck, and esophagus;
also useful in Hodgkin’s lymphoma
• Toxicity Mucocutaneous toxicity and pulmonary
fibrosis, but little myelosuppression
63. Miscellaneous cytotoxic drugs
• Hydroxyurea blocks the conversion of
ribonucleotides to deoxyribonucleotides (interferes
with DNA synthesis); exerts S phase specific action
• Uses chronic myeloid leukaemia, psoriasis,
polycythaemia vera and in some solid tumours.
• Toxicity Myelosuppression
• L-Asparaginase Induce remission in
childhood lymphoblastic leukaemia
• ToxicityLiver damage & allergic reactions
64.
65. Targeted drugs
• These are recently developed drugs which attack
cancer specific target biomolecules or processes
• Targeted drugs can be divided in 2 major types:
1. Specific monoclonal antibodies Attack cell
surface targets or tumor antigens;given parenterally
2. Synthetic compounds which penetrate cells and
affect cancer specific enzymes or processes (active
orally)
66. 1. Tyrosine protein kinase inhibitors Imatinib &
Nilotinib (Inh. ‘Bcr–Abl’ expressed by chronic
myeloid leukaemia cells and related tumours)
2. EGF receptor inhibitors Epidermal growth factor
(EGF) acts on a transmembrane receptor tyrosine
kinase to regulate growth and differentiation of
epithelial cells.
67.
68.
69. • Gefitinib and Erlotinib Penetrate cells & bind to
the tyrosine kinase domain of EGF receptor and
prevent phosphorylation of regulatory proteins.
Effective in lung & pancreatic cancers
• Cetuximab Chimeric monoclonal antibody
directed to the extracellular domain of the EGF
receptor. Its binding interferes with transmembrane
signalling.
• Weekly i.v. infusion of Cetuximab suppresses
advanced/metastatic squamous carcinoma of head
and neck and EGF positive colorectal cancer
70. 3. Angiogenesis inhibitors
• Vascular endothelial growth factor (VEGF)
Most important stimulus for neovascularization
• Bevacizumab Binds to the VEGF rec.
interrupting angiogenic signalling
• Sunitinib Synthetic VEGF receptor 2 inhibitor
• Certain cancers over express VEGF receptor and are
susceptible to these drugs
71. 4. Proteasome inhibitor
• Bortezomib is a unique boron containing compound
that binds to and inhibits ‘proteasomes’, which are
packaged complexes of proteolytic enzymes which
control cell cycle by degrading intracellular
signalling proteins
• Bortezomib thus disrupts many intracellular
signalling pathways, the most important of which
involves the nuclear factor kB (NFkB)
• Multiple myeloma and few other neoplasms
overexpress NFkB and are suppressed by this drug
73. 5. Specific monoclonal antibodies
• Monoclonal antibodies (MAbs) are sourced from
hybridomas created by fusing a continuously
proliferating cell line with antibody producing B
lymphocytes sensitized against a particular antigen
• Malignant cells express certain unique antigens on
their surface
74. • MAbs directed to these antigens have been
produced and tested
• MAbs kill the target cells by following mechanisms
:-
1. Direct signaling of apoptosis
2. Antibody dependent cellular toxicity (ADCC)
3. Compliment dependent cytotoxicity (CDC)
76. Nomenclature of Monoclonal
Antibodies
• Divided into 4 parts Prefix + Target subsystem
+ Origin subsystem + Suffix
• Suffix for all monoclonal antibodies is mab
• Depending on the source of origin, various names
are given, e.g. u stands for human, xi for chimeric
• Target is identified by specific letters, e.g. vi for virus,
ci for circulation
• Prefix is different for each monoclonal antibody
77. • Rituximab Chimerized MAb that binds to the
CD20 B cell antigen which is expressed on the
surface of B lymphocytes and B cell lymphomas
• Rituximab promotes apoptosis in B cell lymphoma,
non Hodgkin lymphoma and chronic lymphocytic
leukaemia
• Has yielded survival benefit to the patients with
these malignancies
78.
79. Hormonal drugs
• Palliative
• Glucocorticoids
1. Used in
1. Acute childhood leukemia and
lymphomas
2. Hodgkin’s disease
3. Hormone responsive breast cancers
2. Induce remission rapidly but relapses occur
inevitably
80. 3.Control complications like hypercalcaemia,
haemolysis and bleeding due to thrombocytopenia
4.Afford symptomatic relief by antipyretic and mood
elevating action
5.Potentiate antiemetic action of Ondansetron or
Metoclopramide
81. • Estrogens Symptomatic relief in carcinoma
prostate; superseded by GnRH agonists used along
with an antiandrogen
• Selective estrogen receptor modulators (tamoxifen),
Selective estrogen receptor down regulator
(Fulvestrant) and Aromatase inhibitors (Letrozole,
etc.) Adjuvant and palliative therapy of carcinoma
breast, as well as for prevention of breast cancer
• Antiandrogen Flutamide & Bicalutamide
antagonize androgen action on prostate carcinoma &
have palliative effect in advanced/metastatic cases
85. • 5-α reductase inhibitor Finasteride & Dutasteride
in advanced carcinoma prostate.
• GnRH agonists Adjuvant/palliative effect in
advanced estrogen/androgen dependent carcinoma
breast/prostate
• Progestins Temporary remission in some cases of
advanced, recurrent (after surgery/radiotherapy) &
metastatic endometrial carcinoma
86.
87. General Principles In
Chemotherapy Of Cancer
1. Selectivity of drugs for the tumor cells is limited:
toxicity is high. As such, measures to enhance
selectivity need to be employed
2. A single clonogenic malignant cell is capable
of producing progeny that can kill the host
3. In any cancer, subpopulations of cells differ in their
rate of proliferation and susceptibility to cytotoxic
drugs.
• These drugs kill cancer cells by first order kinetics,
i.e. a certain fraction of cells present are killed by one
treatment
88. 4.Drug regimens or treatment cycles which can
effectively palliate large tumor burdens may be curative
when applied to minute residual tumor cell population
after surgery and/or irradiation. This is the basis of the
combined modality approach
5.Whenever possible, complete remission should be the
goal of cancer chemotherapy: drugs are often used at
maximum tolerated doses. Intensive regimens used at an
early stage in the disease yield better results.
6.Generally a combination of 2–5 drugs is given in
intermittent pulses to achieve total tumor cell kill,
giving time in between for normal cells to recover
89. • Synergistic combinations and rational sequences are
devised by utilizing:
1. Drugs which are effective when used alone
2. Drugs with different mechanisms of action
3. Drugs with differing toxicities
4. Empirically by trial and error; optimal schedules are
mostly developed by this procedure
5. Kinetic scheduling: on the basis of cell
cycle specificity or nonspecificity of drugs
90. 1. Cell cycle nonspecific Kill resting as well as
dividing cells, e.g. mechlorethamine,
Cyclophosphamide, Chlorambucil,
Carmustine, Dacarbazine, L asparaginase,
Cisplatin, Procarbazine, Actinomycin D.
2. Cell cycle specific Kill only actively dividing
cells. Their toxicity is generally expressed in S
phase.
• These drugs may show considerable phase selectivity
95. 7.Tumors often become resistant to the drug used
repeatedly due to selection of less responsive cells
8.Measures employed to ameliorate the toxicity of
anticancer drugs are:
1. Use of biological response modifiers like
recombinant granulocyte colony stimulating factor
(GCSF) and granulocyte macrophage colony
stimulating factor (GMCSF) Molgramostim,
Filgrastim, hasten recovery of neutrophil count
following myelosuppressant chemotherapy
96. 2.Amifostine provides free thiol radical and reduces
renal toxicity of cisplatin as well as xerostomia due to
radiotherapy
3. Folinic acid rescue can reduce methotrexate toxicity
4.Cystitis caused by Cyclophosphamide can be blocked
by Mesna administered along with it
5.Ondansetron ± dexamethasone, lorazepam,
aprepitant protect against cisplatin (and other emetic
drugs) induced vomiting
6.Hyperuricaemia due to destruction of bulky tumours
can be reduced by allopurinol
97. Therapy of choice for various cancers
Diagnosis Treatment of choice
ALL (Acute
lymphocytic
leukemia)
Induction Vincristine + Prednisolone +
Daunorubicin +
Asparaginase + Intrathecal Methotrexate
Consolidation Hyper-CVAD
[Cyclophosphamide + Vincristine +
Adriamycin (Doxorubicin) +
Dexamethasone] alternated with
Cytarabine + Methotrexate
