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Dr. RAGHU PRASADA M S
DEPT. OF PHARMACOLOGY
SSIMS & RC.
Cancer (Malignant neoplasm) is a class of diseases in
which a group of cells display uncontrolled growth,
invasion, and sometimes metastasis. Cancer affects people
at all ages with the risk for most types increasing with age.
Carcinoma: Epithelial cells; breast, prostate, colon and
Sarcoma: muscle tissue, Connective tissue
Lymphoma and Leukemia: Hemopoietic cells
Germ cell cancer: germ cells- testicle & ovarian cancers
Blastoma: resembles embryonic tissue
Nitrogen mustards -Cyclophosphamide Chlorambucil,
Mechlorethamine , Alkyl sulfonates -Busulfan,
Nitrosoureas -Carmustine, Lomustine
Ethylenimines -Thiotepa Triazenes Dacarbazine
MOA: Cross-linkage Miss- pairing of bases
Cytotoxic agents- alkylation of DNA
Use: Hematologic and solid cancers and used in
A/E: direct vesicant effects, nausea and vomiting after
30-40 min. of injection, Mutagenic.
Mechanism of action:
Hepatic cytochrome P-450 system, enzymes phosphatase
and phosphamidase (activators) aldophosphamide,
which nonenzymatically breaks down to
Phosphoramide mustard (bifunctional) &
Oral bioavailability- 90-100%,
IV injection no local irritation
Half-life -- cyclophosphamide -- 3-10 h; aldophosphamide
-- 1.6 h; phosphoramide mustard -- 8.7 h.
Most metabolized-- < 14% unchanged in urine.
Active on lymphoproliferative diseases, e.g., Hodgkin's
disease and Chronic lymphocytic leukemia
Significant activity against multiple myeloma & ovarian,
breast, small cell lung carcinoma
Combinations- CVP, COP regimen, MOPP regimen
Cystitis, dysuria, fibrosis, hyponatremia
Bone marrow suppression, most important leukopenia
Nausea and vomiting said to be rare
Sterile necrotizing hemorrhagic cystitis(Acrolein)
Sulfur mustard, forms toxic cyclic rthylenimmonium ion
Mechlorethamine 0.4 mg/kg IV, in single or divided
doses. PK: Unstable, solutions- just prior to
administration T 1/2 is 10 min. after IV. Little or no intact
drug excreted in urine.
MOPP, Hodgkin’s, leukemia, lymphosarcoma
A/E: Myelosuppression Leukopenia &
Thrombocytopenia Nausea and vomiting Extravasation
Nitrosoureas: Carmustine , Lomustine, Semustine
MOA: Chloro ethyl moiety- capable of alkylating nucleic
acids and proteins Alkylation and Carbamoylation of DNA.
These agents can kill cells in all phases of the cell cycle
P/K: High lipophilicity Unstable, forming highly reactive
T 1/2 is few min. Renal excretion
Uses -treatment of Hodgkin’s disease, lung cancer
A/E: Bone marrow suppression Leukopenia &
Thrombocytopenia Nausea and vomiting Alopecia ,
Stomatitis , interstitial fibrosis (pulmonary toxicity)
MOA: It is a bifunctional methane sulfonic ester that
forms Intrastrand cross-linkages with DNA.
Palliative treatment of chronic granulocytic leukemia
Busulfan 2–8 mg/d orally; 150– 250 mg/course
P/K: Orally; T 1/2 is <5 min. Excretion in the urine.
Busulfan+ allopurinol prevents excessive uric acid
production from rapid tumor lysis
A/E: Selectively toxic to granulocyte precursors rather
than lymphocytes, interstitial pulmonary fibrosis,
Thrombocytopenia and anemia, gynacomastia
Adverse effects of alkylating agents:
More toxic to bone marrow and gut than to liver and
Infertility to both males and females. (3) Mutagenic. (4)
Develops slowly & may require several genetic/
Folate antagonist Methotrexate
Purine analogues Thioguanine Mercaptopurine
Pyrimidine analogues Cytarabine Fluorouracil
These are structurally related to naturally occurring
compounds , such as vitamins, amino acids, and
nucleotides. These drugs can compete for binding sites
on enzymes or can themselves become incorporated
into DNA or RNA and thus interfere with cell growth
and proliferation .
Folic Acid Analogue, Carrier transport into cell. (2) Binds
strongly to DHFR to deplete THF, Decreases 1-carbon
transfers in Purine synthesis, Decreases [1-C-THF]
intracellular which decreases dUMP dTMP, Therefore,
decreases NUCLEIC ACID synthesis.
Broad range. Well established: (1) Acute Lymphoblastic
Leukemia of childhood. (2) Choriocarcinoma. (3) Cancers
of breast, bladder, and head & neck. (4) Useful in non-
Dose limiting: a) Myelosuppression
(Thrombocytopenia and Leukopenia 7-10 days after Rx,
Recovery 14-21 days). b) GI toxicity (Oral mucositis is
early sign of GI toxicity, Severe mucositis, Small bowel
ulceration & bleeding, Diarrhea -- requires cessation to
prevent perforation of gut )
(2) Nephrotoxicity: Conventional doses, infrequent
toxicity; High doses, toxicity can be severe
Mechanism of action:
(1) Activated by conversion to nucleotide
(2) Inhibits DNA synthesis: Inhibition of Thymidylate
synthase—the most important mechanism of action (MOA)
in rapidly growing tumors (?)
(3) 5-FU Incorporated into RNA: Interfere with RNA
processing - All types, most important MOA in slowly
Clinical Use of 5-FU:
(1) Single agent: Palliative in advanced colorectal carcinoma
(2) Combination: Breast cancer; Carcinomas of ovary,
(3) Sequential MTX + 5-FU: Head and neck cancer
Bone marrow -- esp. with bolus administration.
Leukopenia & Thrombocytopenia ( 9-14 days after start
of Rx, recovery by day 21).
b) GI Toxicity -- esp. with infusion administration. usually
Stomatitis & Diarrhea 4-7 days after treatment
IV bolus: myelosuppression is dominant; Prolonged Rx,
may cause megaloblastic anemia
Hepatotoxicity (elevated transaminases);
myelosuppression less common
MOA: Incorporation of thionucleotide analogue into DNA or
RNA. Feedback inhibition of purine nucleotide synthesis.
PK: slow- oral; T 1/2 is 24 hr ; C max is 6- 8 hr ; M-Liver, E-
Uses: Curative combination chemotherapy for acute
AE: Myelosuppression, leukopenia and thrombocytopenia,
Liver toxicity 2 mg/kg/d orally
MOA: binds actively to tubulin, a class of proteins that
form the mitotic spindle during cell division. Causes
cellular arrest in metaphase.
PLANT DERIVED PRODUCTS: Vincristine and Vinblastine
PK: highly bound to tissues, M-liver and E- bile.
VC: MOPP for Hodgkin’s/non (1.5 mg/m 2 IV / wk. )
VB: testicular, breast & renal(0.1-0.2mg/kg IV/ wk. )
A/E:VC- Alopecia, neurotoxic , no myelosuppression .
VB- bone marrow toxicity, leukopenia, SIADH
All interact with DNA and/or RNA, but may also interact
with other cellular substituents.
Schedule dependence: LESS "phase-specific" than
Tissue necrosis is only generalizable toxicity.
All IV except bleomycin
Mechanism of action:
(1) DNA topoisomerase II inhibitor: Crucial to DNA
replication and transcription.
(2) Traditional explanations of MOA: a) intercalates
between base pairs of DNA and inhibits DNA-dependent
RNA synthesis. b) Generates free radicals that cause
membrane damage and DNA strand breaks.
Broad spectrum anti-cancer activity.
Hodgkin's disease, non-Hodgkin's lymphomas,
sarcomas, acute leukemia, and breast, lung, and
ovarian carcinomas all responsive
Activity observed in bladder tumors, and carcinomas of
prostate, thyroid, endometrium, head and neck, and
other solid tumors
Local Toxicity -- Radiation Recall
Interaction of doxorubicin and radiation in some
tissues to produce enhanced reactions.
Reactions include: a) Skin: ulceration and necrosis. b)
Pulmonary fibrosis and sloughing of esophageal
mucosa. c) Heart, and intestinal mucosa may also be
Three categories of toxicity: a) Local toxicities. b) Acute
toxicities. c) Chronic toxicity
(1) Local Toxicity – Extravasation (Severe local tissue
a) Hematologic: Leukopenia with 7-10 days;
recovery typically by 21 days; Thrombocytopenia
and anemia less common
b) If given too fast: "Histamine-release" syndrome;
Cardiac arrest preceded by ECG changes
a) Cardiomyopathy and congestive heart failure:
require cessation of treatment
Progestational agents have been used as second-line
hormonal therapy for metastatic hormone-dependent
breast cancer and endometrial carcinoma previously
treated by surgery and radiotherapy.
Progestins stimulate appetite and restore a sense of
well-being in cachectic patients with advanced stages
of cancer and acquired immunodeficiency syndrome
Medroxyprogesterone intramuscularly in doses of 400-
1000 mg weekly
Selective Estrogen-Receptor Modulators(SERMs)
High doses of estrogen have long been recognized as
effective treatment of breast cancer. for 8-12 weeks
Tamoxifen citrate is the most widely
studied anti-estrogenic treatment in breast cancer
prevents the development of breast cancer in women at
high risk prior nonmalignant breast
pathology, or inheritance of the BRCA1 or BRCA2 genes.
ADR-Vasomotor symptoms (hot flashes), atrophy of the
lining of the vagina, hair loss, nausea, and
MOA: it binds actively to Estrogen receptors and
competes with endogenous estrogens for the clinical
sites. Inhibits the growth of ovarian, uterus and breast
PK: orally, T max is 4-7 hr , M- hydroxylation and
glucuronidation, E- in feces.
Synthetic anti-estrogen used in the treatment of breast
A/E: Hot flushes, mild nausea, exacerbation, bone
Selective Estrogen Receptor Downregulators(SERDs)
pure anti-estrogens- fulvestrant
Fulvestrant is used for postmenopausal women with
hormone receptor positive metastatic breast cancer
Anastrozole and letrozole nonsteroidal imidazoles
are used as part of the standard of care for treatment
of early-stage and advanced breast
cancer in postmenopausal women
Gonadotropin-Releasing Hormone Agonists and
GnRH agonists -leuprolide, goserelin, triptorelin,
histrelin and buserelin GnRH agonist will
deplete testicular androgens, while the anti-androgen
component competes at the receptor with residual
androgens made by the adrenal glands.
GnRH antagonist- Abarelix
rapidly achieves medical castration
ADR-local reactions and anaphylaxis
Anti-androgens-Cyproterone and Megestrol
Anti-androgens bind to ARs and competitively inhibit the
binding of testosterone and dihydrotestosterone
Advanced prostate cancer
Flutamide and Bicalutamide-
Advanced prostate cancer
MOA: Inhibits Asparginase synthase enzyme. L-
Asparginase catalyzes the hydrolysis of L- Aspargine to
Aspartic acid and ammonia. Inhibits protein synthesis –
PK: Derived from E.coli , T 1/2 is 6-30 hr , M-by serum
proteases and RES,
Uses Acute lymphoblastic Leukemia, Combination
therapy, non-lymphocytic cancers.
A/E: Hyper sensitivity, Nausea, anorexia, wt loss,
hepatotoxic, hyperglycemia Pancreatitis,
MOA: binds to DNA at N7, O6 of Guanine, and causes
cross linkage producing alterations in DNA structure and
inhibition of DNA synthesis. Cytotoxic effect similar to
P/K: orally, extensively binds to proteins, T-max is 4-7 hr,
T 1/2 is 2-4 days. M- hydroxylation and glucuronidation,
E-renal. Testicular and Ovarian cancer.
A/E: Renal toxicity, severe nausea and vomiting, hearing
loss in high frequencies (4000Hz), mild bone marrow
IMATINIB -Acts by inhibiting the Philadelphia
chromosome(bcr-abl kinase) and is very useful in the
treatment of chronic myelogenous leukemia (CML).
Remissions in CML patients are achieved with high
frequency and very low toxicity.
GIST-Gastro-Intestinal Stromal tumors
RITUXIMAB: acts against CD20 on cell surfaces (normal
Non Hodgkin's lymphoma 375mg/m2, IV. AE:
Hypotension, Dizziness, Anxiety, Nausea, Diarrhea,
Bone marrow depression.
GEMTUZUMAB: acts against CD33 with drawn from
Acute Myeloid Leukemia 9 mg/m2, IV AE: chills, fever,
nausea, vomiting, hypoxia, dyspnea, bone marrow
FILGRASTIM: rG -CSF Acts on precursor hematopoietic
cells in the bone marrow by binding to specific
receptors that stimulate cellular proliferation and
differentiation into neutrophils .
Filgrastim accelerates recovery of neutrophils after
Drug is well tolerated mild to moderate bone pain.
Defective activation: Cyclophosphamide requires
metabolic activation, Methotrexate conversion to more
active MTX-polyglutamate in cells
Increased inactivation: e.g., aldehyde dehydrogenase
converse cyclophosphamide to inactive metabolite.
Altered nucleotide pools: Can occur with
Altered DNA repair: Repair mechanisms increased, i.e.,
ability to remove cross-links, Affect the action of
bleomycin and other DNA-directed drugs
Altered target: Less affinity for drug, Methotrexate
(Dihydrofolate reductase changes ).
Decreased target: decreased topoisomerase II, e.g.,
Gene amplification: Methotrexate (MTX) increase
dihydrofolate reductase, hence Requires more MTX to
Decreased accumulation: Decreased uptake
(Methotrexate -- carrier protein decreases). Increased
Efflux (Multidrug Resistance, P-Glycoprotein (gP-170)
in membrane, pumps drug out)
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