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ANTI-CANCER DRUGS: ALL YOU NEED TO KNOW

ANTI-CANCER DRUGS: ALL YOU NEED TO KNOW. PRESENTED BY: VISHNU.R.NAIR, 5 TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP). GENERAL INTRODUCTION. Since neoplastic(cancer) cells resemble to normal cells in many respects  drugs used to kill tumor cells, MAY ALSO KILL NORMAL CELLS

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ANTI-CANCER DRUGS: ALL YOU NEED TO KNOW

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  1. ANTI-CANCER DRUGS: ALL YOU NEED TO KNOW PRESENTED BY: VISHNU.R.NAIR, 5TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).

  2. GENERAL INTRODUCTION

  3. Since neoplastic(cancer) cells resemble to normal cells in many respects  drugs used to kill tumor cells, MAY ALSO KILL NORMAL CELLS • Since most anti-cancer agents act on RAPIDLY-DIVIDING CELLS  normal cells, with QUICK TURNOVER  are most susceptible to toxicity  lead to side-effects like: • Bone marrow suppression • Alopecia • Mucositis, etc. • Newer drugs  target “specific steps in cell cycle”  devoid of above adverse effects.

  4. Based on which stage of cell-cycle the drugs inhibit  anti-cancer agents are classified as: • CCS (Cell-cycle specific) drugs: • Effective, when the cells are PROLIFERATING B. CCNS(Cell-cycle non-specific) drugs: • Effective, when the cells are DIVIDING/ in RESTING phase.

  5. THEORIES BEHIND ANTI-CANCER ACTIVITY

  6. Initially  anticancer agents were developed, based on “MURINE L1210 LEUKEMIA MODEL” • According to this model  growth fraction of 100% was observed  led to the conclusion that “all cells are actively-dividing” • Based on this murine model  “CYTOTOXIC DRUGS ACT WITH FIRST-ORDER KINETICS” , which means that “a constant proportion of cells are killed with a given dose, rather than constant number of cells” • HUMAN SOLID TUMORS  do not follow above model, since growth fraction of the tumor is “not constant”, but “decreases exponentially with time”. • According to GOMPERTZIAN MODEL  “growth fraction peaks when tumor is approximately 37% of its maximum size .”

  7. EFFECTS OF ANTI-CANCER AGENTS ON DIFFERENT CELL-CYCLE STAGES

  8. As we know  there are 4 phases of cell-cycle: • G1 Phase • S Phase • G2 Phase • M phase • Anti-cancer agents  act on different stages of cell-cycle

  9. DRUGS, THAT ACT ON G1 PHASE: • CCS DRUGS: • Etoposide B. DRUGS, THAT ACT ON S-PHASE: • CCS DRUGS: • Antimetabolites(MTX, 6-MP, 5-FU, Cladribine, Capecitabine) • CCNS DRUGS: i. Alkylating agents( Melphalan, cyclophosphamide, nitrosourea) ii. Platinum compounds(Cisplatin, oxaliplatin, carboplatin)

  10. C. DRUGS, ACTING ON G2 PHASE: • CCS DRUGS: • Topoisomerase inhibitors(irinotecan, topotecan, etoposide) • Bleomycin • CCNS DRUGS: • Anthracyclines( Doxorubicin, daunorubicin, epirubicin, mitoxantrone) D. DRUGS, ACTING ON M-PHASE: • CCS DRUGS: • Vinca alkaloids(vincristine, vinblastine, vinorelbine) • Taxanes (paclitaxel, docetaxel, cabazitaxel)

  11. iii. Erbulin iv. Estramustine v. Ixabepilone. • CCNS DRUGS: • Antitumor antibiotics(Dactinomycin, Mitomycin-C)

  12. CLASSIFICATION OF ANTI-CANCER AGENTS

  13. Anti-cancer agents are classified into the following headings: • ALKYLATING AGENTS • PLATINUM COMPOUNDS • ANTI-METABOLITES • NATURAL PRODUCTS • HORMONES & RELATED AGENTS.

  14. ALKYLATING AGENTS

  15. Alkylating agents are classified as: • NITROGEN MUSTARDS(Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil) • ETHYLENIMINES(Thio-TEPA, Hexamethylmelamine(altretamine) • ALKYL SULFONATES(Busulfan) • NITROSOUREAS(Carmustine, lomustine, streptozocin) • TRIAZINES(Procarbazine, dacarbazine, temozolomide)

  16. All alkylating agents & related drugs (procarbazine, dacarbazine & platinum compounds)  are CCNS drugs  thus, they act on resting, as well as dividing cells • Drugs  alkylate nucleophilic groups on DNA bases(N7 of guanine)  leads to: • Cross-linkage of bases • Abnormal base-pairing • DNA-strand breakage • Major ADRs include: • GI distress e. Sterility. • Bone marrow suppression • Alopecia • Secondary leukemias

  17. NITROGEN MUSTARDS: CYCLOPHOSPHAMIDE: • Prodrug  converted by hepatic biotransformation to “aldophosphamide” • Degradation product of cyclophosphamide is ‘acrolein”  leads to “hemorrhagic cystitis” • Risks of hemorrhagic cystitis can be reduced by: • Vigorous hydration • Use of MESNA(mercapto ethane sulfonic acid) • Other side effects of cyclophosphamide include: • Cardiac dysfunction c. SIADH • Pulmonary fibrosis

  18. IFOSFAMIDE: • Drug  produces 2 metabolites: • Acrolein(causes hemorrhagic cystitis) • Chloracetaldehyde(nephrotoxic) - Although ifosfamide has same ADR profile as that of cyclophosphamide  former has HIGHER RISKS OF NEUROTOXICITY & HEMORRHAGIC CYSTITIS!! - CYCLOPHOSPHAMIDE is DOC for WEGENER’S GRANULOMATOSIS • MECHLORETHAMINE is mainly used for HODGKIN’S DISEASE • MELPHALAN is DOC for MULTIPLE MYELOMA.

  19. NITROSOUREAS: • Carmustine, lomustine & semustine highly lipid-soluble  can cross BBB  can be used for treatment of BRAIN TUMORS like GLIOMAS • Can cause DELAYED NEUTROPENIA • Dacarbazine differs from other alkylating agents, in that it primarily affects RNA & protein synthesis. • STREPTOZOCIN: • Drug  destroys beta-cells of pancreas  useful for ISLET-CELL TUMORS • Minimum risks of BMT.

  20. OTHER ALKYLATING AGENTS: BUSULFAN: • Causes ADRENAL INSUFFICIENCY, PULMONARY FIBROSIS, SKIN HYPERPIGMENTATION & HYPERURICEMIA PROCARBAZINE: • Most Leukemiogenic!!!! • Causes DISULFIRAM-LIKE INTERACTION with ALCOHOL • Also leads to CNS effects like HYPNOSIS, VIVID DREAMS, etc. CHLORAMBUCIL: • Drug  spares myelocytes • Used for CLL!

  21. DISTINCTIVE TOXICITIES OF ALKYLATING AGENTS:

  22. IMPORTANT POINTS ABOUT AKLYLATING AGENTS!! • NITROSOUREAS & IFOSFAMIDE  can lead to RENAL FAILURE! • All alkylating agents are MYELOSUPPRESSIVE • NITROSOUREAS & MECHLORETHAMINE  possess strong “VESICANT PROPERTIES”  can cause local irritation & damage! • Can lead to STERILITY & SECONDARY LEUKEMIAS(less common with CYCLOPHOSPHAMIDE) • All agents cause PULMONARY FIBROSIS • In high dose  they can lead to HEPATIC VENO-OCCLUSIVE DISEASE(HVOD)  can be reversed by DEFIBROTIDE SODIUM!

  23. PLATINUM COMPOUNDS

  24. Include CISPLATIN, CARBOPLATIN & OXALIPLATIN • Although they are not ‘alkylating agents’  they possess similar MOA as that of alkylating agents. • Only difference is that platinum compounds use “PLATINUM” instead of “ALKYL GROUP” to form DNA dimers. • They are the drugs that cause MAXIMUM EMESIS issues! • Other effects of platinum compounds include: • Mild BMT • Ototoxicity • Neurotoxicity • Nephrotoxicity • CISPLATIN is most nephrotoxic • CARBOPLATIN is most HEMOTOXIC(causes maximum BMT)

  25. CARBOPLATIN has lesser nephrotoxic, ototoxic & neurotoxic effects compared to CISPLATIN • OXALIPLATIN  used, when cells show resistance to CISPLATIN/CARBOPLATIN • Dose-limiting toxicity of OXALIPLATIN is NEUROTOXOCITY(Peripheral neuropathy) • In order to prevent NEPHROTOXICITY  perform CHLORIDE DIURESIS before CISPLATIN THERAPY • CHLORIDE DIURESIS  ineffective in prevent OTOTOXICITY! • CISPLATIN  should always be given as SLOW I.V INFUSION(and NOT BOLUS) to prevent: • Intense N&V • Acute rise in serum creatinine. • Since ALUMINIUM  inactivates CISPLATIN  aluminium-containing equipments/needles should NOT be used with CISPLATIN!

  26. In order to prevent cisplatin-induced NEPHROTOXICITY  AMIFOSTINE can be given • Other applications of AMIFOSTINE include: • Reduction of XEROSTOMIA in patients, undergoing irradiation of head & neck(involving parotid glands) • To reduce incidence of neutropenia-related fever & infections caused by alkylating agents & cisplatin • CISPLATIN  has lesser risks of causing BMT!! • CISPLATIN  reduces concentration of maximum ions in serum  leads to: • Hypokalemia • Hypocalcemia • Hypomagnesemia • Hypophosphatemia • CISPLATIN  also can cause AML(Usually 4 years/ more after treatment!)

  27. ANTI-METABOLITES

  28. ANTI-METABOLITES are classified as: • PYRIMIDINE ANALOGS: 5-FU, Cytarabine, Gemcitabine • PURINE ANALOGS: 6-MP, 6-thioguanine, pentostatin, cladribine • FOLIC ACID ANALOGS: MTX, Pemetrexed, Pralatrexate.

  29. Since these drugs act in the S-PHASE of cell-cycle  they are CCS DRUGS, meaning that they act ONLY AGAINST DIVIDING CELLS! • Possess IMMUNOSUPPPRESSIVE properties, other than that of ANTINEOPLASTIC EFFECTS

  30. FOLIC ACID ANALOGS: • Actions include: • Inhibition of DIHYDROFOLATE REDUCTASE • Inhibition of THYMIDYLATE SYNTHASE & other enzymes, involved in early purine synthesis • MTX  forms POLYGLUTAMATES inside the cell  helps to trap the drug within the cells  causes cytotoxicity to neoplastic cells • CAUSES OF MTX RESISTANCE??? • Impaired transport of MTX into cells • Production of altered forms of DHFRase  possess reduced affinity for the inhibitor • Increased concentration of intracellular DHFRase (via gene amplification/ altered gene regulation)  reduce ability to synthesize MTX POLYGLUTAMATES

  31. d. Increased expression of “drug efflux transporter” of MRP(Multidrug resistant protein) class. • Since clearance of MTX  depends on renal function  VIGOROUS HYDRATION is required to prevent DRUG CRYSTALLIZATION in RENAL TUBULES!! • ADRs of MTX include: • BMT • Mucositis • Hepatotoxicity(long term use) • Pulmonary fibrosis(long-term use) • Toxicity of MTX to normal cells can be reduced by administration of “N10 formyl-tetrahydrofolic acid”(folinic acid, citrovorum factor/ leucovorin) • Above strategy  known as “LEUCOVORIN RESCUE”

  32. In extreme cases  MTX toxicity can be treated by : • Dialysis • Administration of GLUCARPIDASE(MTX-cleaving enzyme) • MTX toxicity can also be reduced by URINE ALKALINIZATION • NSAIDS, penicillins, cephalosporins  reduce renal excretion of MTX  can result in toxicity!! • PEMETREXED : • Approved for treatment of treatment of MESOTHELIOMA • Use of FOLIC ACID & VITAMIN B12 SUPPLEMENTATION  reduce pemetrexed toxicity, without interfering with its clinical efficacy! • PRALATREXATE  indicated for PERIPHERAL T-CELL LYMPHOMA.

  33. HOW TO REMEMBER USES OF MTX?? Use the code “Inhibit CANCER”!!

  34. PURINE ANALOGS: • 6-MP & 6-TG are the purine anti-metabolites  activated by HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE (HGPRTase)  resulting nucleotides inhibit several enzymes involved in PURINE BIOSYNTHESIS & METABOLISM • 6-MP is metabolized by XANTHINE OXIDASE! • When given along with ALLOPURINOL(xanthine oxidase inhibitor)  dose of 6-MP (& also azathioprine), SHOULD BE REDUCED to 1/4thof ORIGINAL DOSE!! • Used mainly for treatment of AML & CML • Dose-limiting toxicity is BMT • Hepatotoxicity may also occur • Since CLADRIBINE is resistant to degradation by “adenosine deaminase”  it is the DRUG OF CHOICE for HAIRY CELL LEUKEMIA • All purine analogs may cause immunosuppression(on long-term use)  thus, patients should be given COTRIMOXAZOLE for prophylaxis of Pneumocystis jiroveci-induced pneumonia!

  35. FLUDARABINE PHOSPHATE: • DOC for CLL • FLUDARABINE + PENTOSTATIN  increased risk of pulmonary toxicity! • 6-MP & 6-TG  metabolized by THIOPURINE METHYL TRANSFERASE(TPMT)

  36. PYRIMIDINE ANALOGS: • Drugs include CYTARABINE, 5-FU, CAPECITABINE, GEMCITABINE, 5-AZACYTIDINE & DECITABINE • CYTARABINE: • Single most effective agent for inducing remission in AML!! • Drug  activated by kinases to form “arabinoside CTP”  inhibits DNA polymerase • High dose of drug  leads to neurotoxicity(ataxia, peripheral neuropathy) • 5-FU : • Converted to 5’-DUMP inhibits thymidylate synthase • Metabolized by conversion to carbon-dioxide  eliminated by respiratory pathway • Catabolized by DIHYDROPYRIMIDINE DEHYDROGENASE(DPD)

  37. d. Can lead to “HAND & FOOT SYNDROME”(form of ERYTHROMELALGIA, manifested as tingling, numbness, pain, erythema, swelling & increased pigmentation) e. URIDINE TRIACETATE  given orally for treatment of 5-FU toxicity f. Leucovorin  augments its action! g. 5-FU  causes single-strand breaks  thus affects both DNA & RNA • CAPECITABINE: • Oral pro-drug of 5-FU • Can cause hyperbilirubinemia • URIDINE TRIACETATE  given for capecitabine toxicity

  38. GEMCITABINE: • Very potent radiosensitizer • DOC for PANCREATIC CANCER! • 5-AZACYTIDINE: • Acts by DNA hypomethylation • Approved for treatment of MYELODYSPLASIA - DECITABINE also acts by similar mechanisms as that of 5-azacytidine!

  39. DISTINCTIVE TOXICITIES OF ANTI-METABOLITES:

  40. MAJOR DIFFERENCE BETWEEN ALKYLATING AGENTS & ANTIMETABOLITES???? ALKYLATING AGENTS  mainly used for CHRONIC LEUKEMIAS ANTI-METABOLITES  mainly used for ACUTE LEUKEMIAS!!!

  41. MITOTIC SPINDLE INHIBITORS

  42. Include: • VINCA ALKALOIDS(Vincristine, vinblastine, vinorelbine) • TAXANES(Paclitaxel, docetaxel, cabazitaxel) • IXABEPILONE • ERBULIN MESYLATE • ESTRAMUSTINE.

  43. VINCA ALKALOIDS: • Drugs  inhibit formation of mitotic spindle  inhibit microtubule polymerization • Effective in M-phase of cell-cycle • Can cause SIADH • Vinblastine causes BMT • Although vincristine is “marrow-sparing”  it can cause “neurotoxicity” (peripheral neuropathy) • VINBLASTINE is used in METASTATIC TESTICULAR TUMORS • VINCRISTINE (along with GLUCOCORTICOIDS)  treatment of choice for inducing remission in CHILDHOOD LEUKEMIAS • Other uses of VINCRISTINE include: • Pediatric solid tumors(Wilm’s tumor, neuroblastoma, rhabdomyosarcoma) • Lymphomas.

  44. B. TAXANES: • PACLITAXEL & DOCETAXEL  prevent disassembly of microtubules  interfere with mitotic spindle formation • Paclitaxel  causes hypersensitivity reactions (due to Cremophore-containing vehicle) • Docetaxel  is devoid of above adverse effect • Since paclitaxel has risks of hypersensitivity reactions  protein-bound paclitaxel(Nab-paclitaxel) is used • Both paclitaxel & docetaxel can cause BMT & neurotoxicity • CISPLATIN  reduces PACLITAXEL clearance • PACLITAXEL  reduces DOXORUBICIN clearance • (CABAZITAXEL + PREDNISONE) combination  used for hormone refractory metastatic prostate cancer.

  45. C. IXABEPILONE: • Newer molecule, approved for treatment of ADVANCED BREAST CARCINOMA, that is resistant to anthracyclines & taxanes • Given in combination with CAPECITABINE • Drug  binds to tubulin  promotes microtubule stabilization  arrests cells in the G2-M phase of cell cycle.

  46. D. ERBULIN MESYLATE: • Microtubule inhibitor • Approved for treatment of METASTATIC BREAST CANCER • Also indicated in LIPOSARCOMA.

  47. E. ESTRAMUSTINE: • Combination of ESTROGEN & MECHLORETHAMINE • Used for treatment of PROSTATE CARCINOMA • Produces anti-mitotic effects, by binding to tubulin • Can produce estrogenic side-effects, like: • Gynecomastia • Impotence.

  48. TOPOISOMERASE INHIBITORS

  49. Includes: • CAMPTOTHECINS: Irinotecan, topotecan • EPIPODOPHYLLOTOXINS: Etoposide, teniposide • ANTITUMOR ANTIBIOTICS: Doxorubicin, daunorubicin, mitoxantrone, epirubicin, dactinomycin, bleomycin, mitomycin.

  50. CAMPTOTHECINS: • Obtained from tree named “Camptotheca acuminata” • Topoisomerase I  produces nicks, introduces negative supercoils & reseals the DNA strand • Camptothecins  inhibit Topoisomerase I • TOPOTECAN: • Used in advanced ovarian carcinoma • Excreted via renal route • Dose-limiting toxicity includes NEUTROPENIA.

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