Class anticancer drugs

this class is in brief for undergraduate understanding and examination purpose

1. CLASS ANTICANCER DRUGS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1

2. ANTI CANCER AGENTS 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 Lung cancers. Sarcoma : muscle tissue, Connective tissue Lymphoma and Leukemia : Hemopoietic cells Germ cell cancer: germ cells- testicle & ovarian cancers Blastoma : resembles embryonic tissue

3. ANTI CANCER AGENTS Alkylating agents Nitrogen mustards -Cyclophosphamide Chlorambucil Alkyl sulfonates - Busulfan Nitrosoureas- Carmustine , Lomustine Ethylenimines- Thiotepa Triazenes- Dacarbazine Antimetabolites Folate antagonist - Methotrexate Purine analogues -Thioguanine Mercaptopurine Fludarabine Pyrimidine analogues -Cytarabine Fluorouracil

4. ANTI CANCER AGENTS Antibiotics Anthracyclines Doxorubicin hydrochloride Daunorubicin Bleomycin sulfate C . Mitomycin Dactinomycin ( Actinomycin D) Plicamycin Plant derived products Vinca alkaloids Vincristine Vinblastine Epipodophyllotoxins Etoposide Teniposide Taxanes paclitaxel, docetaxel

5. ANTI CANCER AGENTS Hormonal agents Glucocorticoids- Prednisolone Estrogens, anti-estrogens- Tamoxifen, Estramustine Androgens , anti-androgens Flutamide Progestins – hydroxy progeseterone acetate Luteinizing hormone–releasing hormone (LH-RH) antagonists - Buserelin Leuprolide Immuno modulators Levamisole Interferons Interferon alfa-2a and 2 b Interleukins - Aldesleukin Monoclonal antibodies Rituximab, Alemtuzumab Ibritumomab, Gemtuzumab

6. ANTI CANCER AGENTS Miscellaneous agents Hydroxyurea Procarbazine Mitotane Cisplatin Carboplatin Mitoxantrone Cellular growth factors -Filgrastim, Sargramostim Enzymes- L- Asparaginase

7. ALKYLATING AGENTS Nitrogen mustards -Cyclophosphamide Chlorambucil, Mechlorethamine , Alkyl sulfonates -Busulfan, Nitrosoureas -Carmustine , Lomustine Ethylenimines -Thiotepa Triazenes Dacarbazine MOA : Cross-linkage Miss- pairing of bases Depurination Cytotoxic agents- alkylation of DNA Use : Hematologic and solid cancers and used in combination therapy. A/E : direct vesicant effects, nausea and vomiting after 30-40 min. of injection, Mutagenic .

8. Nitrogen mustards- Cyclophosphamide Mechanism of action: Hepatic cytochrome P-450 system, enzymes phosphatase and phosphamidase (activators)  aldophosphamide , which nonenzymatically breaks down to  Phosphoramide mustard (bifunctional) & Acrolein(cytotoxic) Pharmacokinetics: 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.

9. Nitrogen mustards Cycloposphamide 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 Adverse effects: Cystitis, dysuria, fibrosis, hyponatremia Bone marrow suppression, most important leukopenia and thrombocytopenia Nausea and vomiting said to be rare Sterile necrotizing hemorrhagic cystitis(Acrolein)

10. Nitrogen mustards 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

11. Nitrosoureas 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 decomposition products; 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)

12. Alkyl sulphonates Busulfan 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

13. Alkylating agents Adverse effects of alkylating agents: More toxic to bone marrow and gut than to liver and kidney, Infertility to both males and females. (3) Mutagenic. (4) Carcinogenic. Tumor resistance: Develops slowly & may require several genetic/ biochemical changes

14. ANTIMETABOLITES Folate antagonist Methotrexate Purine analogues Thioguanine Mercaptopurine Fludarabine 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 .

15. Folate Antagonists- METHOTREXATE 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 . Clinical Uses: Broad range. Well established: (1) Acute Lymphoblastic Leukemia of childhood. (2) Choriocarcinoma. (3) Cancers of breast, bladder, and head & neck. (4) Useful in non-Hodgkin's lymphomas

16. METHOTREXATE Adverse effects: 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 (3) Immunosuppression. (4) Hepatotoxicity.

17. Pyramidine antagonist Fluorouracil (5-FU) 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 growing tumors. Clinical Use of 5-FU: (1) Single agent: Palliative in advanced colorectal carcinoma (2) Combination: Breast cancer; Carcinomas of ovary, stomach, pancreas (3) Sequential MTX + 5-FU: Head and neck cancer

18. Fluorouracil (5-FU) Adverse effects: 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

19. Purine Analogues Thioguanine 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- renal. Uses : Curative combination chemotherapy for acute myelogenous leukemia. AE : Myelosuppression, leukopenia and thrombocytopenia , Liver toxicity 2 mg/kg/d orally

20. Vinca alkaloids 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

21. Antitumor Antibiotics All interact with DNA and/or RNA, but may also interact with other cellular substituents. Schedule dependence: LESS "phase-specific" than antimetabolites. 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.

22. Antitumor Antibiotics Doxorubicin(Adriamycin) Clinical Indications: 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

23. Antitumor Antibiotics Adverse effects: 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 affected Three categories of toxicity: a) Local toxicities. b) Acute toxicities. c) Chronic toxicity (1) Local Toxicity – Extravasation (Severe local tissue necrosis)

24. Antitumor Antibiotics Adverse effects: Acute Toxicities 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 Chronic Toxicities a) Cardiomyopathy and congestive heart failure: require cessation of treatment

25. Hormonal anticancer agents PROGESTINS 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 ( AIDS) Medroxyprogesterone intramuscularly in doses of 400-1000 mg weekly

26. Hormonal anticancer agents 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 vomiting.

27. HORMONE DERIVATIVES: Tamoxifen MOA: it binds actively to Estrogen receptors and competes with endogenous estrogens for the clinical sites. Inhibits the growth of ovarian, uterus and breast cancer cells. PK : orally, T max is 4-7 hr , M- hydroxylation and glucuronidation, E- in feces. Synthetic anti-estrogen used in the treatment of breast cancer. A/E : Hot flushes, mild nausea, exacerbation, bone pain, Hypercalcaemia

28. Hormonal anticancer agents Selective Estrogen Receptor Downregulators (SERDs) pure anti-estrogens- fulvestrant Fulvestrant is used for postmenopausal women with hormone receptor positive metastatic breast cancer AROMATASE INHIBITORS 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

29. Hormonal anticancer agents Gonadotropin-Releasing Hormone Agonists and Antagonists 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

30. Hormonal anticancer agents Anti-androgens- C yproterone and M egestrol Anti-androgens bind to ARs and competitively inhibit the binding of testosterone and dihydrotestosterone A dvanced prostate cancer NONSTEROIDAL ANTI-ANDROGENS Flutamide and Bicalutamide - Advanced prostate cancer

31. ENZYMES: L-Asparaginase MOA: Inhibits Asparginase synthase enzyme. L- Asparginase catalyzes the hydrolysis of L- Aspargine to Aspartic acid and ammonia. Inhibits protein synthesis – cell death. 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,

32. Platinum analogues-Cisplatin 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 alkylating agents 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 toxicity.

33. IMATINIB 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 N eurofibramatosis

34. MONOCLONAL ANTIBODIES RITUXIMAB : acts against CD20 on cell surfaces (normal and malignant) Non Hodgkin's lymphoma 375mg/m2, IV. AE: Hypotension, Dizziness, Anxiety, Nausea, Diarrhea, Bone marrow depression. GEMTUZUMAB : acts against CD33 with drawn from market Acute Myeloid Leukemia 9 mg/m2, IV AE: chills, fever, nausea, vomiting, hypoxia, dyspnea, bone marrow depression.

35. CELLULAR GROWTH FACTORS FILGRASTIM 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 chemotherapy. Drug is well tolerated mild to moderate bone pain.

36. Combination chemotherapy MOPP-Mechlorethamine+ Vincristine ( Oncovin ), Procarbazine+ Prednisolone -for hodgkins lymphoma COAP- Cyclophosphamide + Oncovin (Vincristine) Ara -C( cytarabine )+ Prednisolone -for acute lymphoblastic lymphoma ABVD- Adriamycin(Doxorubicin) + Bleomycin+ Vinblastine+ Dacarbazine for hodgkins lymphoma POMP- Prednisolone+Oncovin+Methotrexate + Purinethol (6-MP) for ALL

37. Anticancer agents Resistance mechanism 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 antimetabolites. Altered DNA repair : Repair mechanisms increased, i.e., ability to remove cross-links, Affect the action of bleomycin and other DNA-directed drugs

38. Anticancer agents Resistance mechanism Altered target : Less affinity for drug, Methotrexate (Dihydrofolate reductase changes ). Decreased target : decreased topoisomerase II, e.g., etoposide Gene amplification: Methotrexate (MTX) increase dihydrofolate reductase, hence Requires more MTX to block 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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