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Anticancer drugs - drdhriti

A Power point presentation on "Anticancer Drugs" compiled for theory lecture to the Undergraduate level Medical Students

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Anticancer drugs - drdhriti

  2. 2. Introduction The anticancer drugs either kill cancer cells or modify their growth – but, selectivity of these drugs limited – damages normal cells too ….. TOXICITY
  3. 3. Introduction No Treatment: Before 1940 (Nitrogen mustard) ◦Rapid progress since then Surgery: before 1955 Radiotherapy: 1955 - 1965 Chemotherapy: after 1965 Immunotherapy, Hormone therapy , stem cell transplant and Gene therapy Innovations: Target growth factors, specific signaling pathways, angiogenesis and tumour antigen etc.
  4. 4. Aims of Therapy Cure or induce prolonged ‘remission’ so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persist - Acute Lymphoblastic Leukaemia, Wilm`s tumor, Ewing`s sarcoma, Retinoblastoma and Rhabdomyosarcome etc. in children ◦ Hodgkin`s lymphoma, testicular teratoma, seminoma and choriocarcinoma etc. Palliation: Shrinkage of evident tumour, alleviation of symptoms and prolongation of life - Breast cancer, ovarian cancer, endometrial carcinoma, CLL, CML, small cell cancer of lungs and Non-Hodgkin lymphoma ◦Insensitive or less sensitive but life may or may not be prolonged - Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer
  5. 5. Aim of Therapy – contd. Adjuvant therapy: One of the main basis of treatment now ◦ For mopping up of residual cancer cells including metastases after Surgery, Radiation and immunotherapy etc. Routinely used now Mainly in solid tumours – combined modality approach
  6. 6. Cancer Chemotherapy – 5 years survival rate Childhood Acute Lymphoblastic Leukemia 50 - 80% Acute Adult Lymphoblastic Leukemia 20 - 60% Childhood Acute Myeloblastic Leukemia 20 - 60% Adult Acute Myeloblastic Leukemia 10 - 20% Breast Cancer 5 - 20% Hodgkin’s lymphoma 40 - 80%
  7. 7. General Toxicities Harmful to normal tissues – rapidly multiplying cells (drug targets – nucleic acid synthesis) - particularly to GI mucosa, Bone marrow, RE system and gonads and hair cells Steep dose response curve Low therapeutic index Effects are in dose dependent manner
  8. 8. Toxicities – Immunity and Infections Bone marrow depression (at therapeutic doses): Agranulocytopenia, agranulocytosis, thrombocytopenia and aplastic anaemia etc. – Infection and Bleeding - often limits treatment Lymphoreticular system: Lymphocytopenia and inhibition of lymphocyte function – suppression of CMI and humoral immunity ◦Epithelial damage + above 2 - - susceptibility to infections ◦Fungi – Candida; Viruses – Herpes zoster and CMV; Toxoplasma and Pneumocystis jiroveci
  9. 9. Toxicities of anticancer – contd. •Oral cavity: Buccal mucosa - High epithelial turnover - stomatitis • Regular minor trauma to oral mucosa and gums + presence of high oral microflora + lowered immunity – increased oral infections • Xerostomia – dental carries • Bleeding of gums •GIT: Diarrhoea, shedding of mucosa, haemorrhage – decrease in rate of renewal • Nausea, vomiting – CTZ direct stimulation and generation of emetic impulses/mediator from Upper GIT •Skin: alopecia •Gonads: oligospermia, impotence, amenorrhea and infertility •Foetus: Abortion, fetal death and teratogenicity
  10. 10. Toxicities of anticancer – contd. Carcinogenicity: leukaemias and lymphomas Hyperuricaemia: Uric acid- Purine metabolism - Acute renal failure, gout and lithiasis Specific toxicities: Neuropathy, myopathy, cystitis, alopecia etc.
  11. 11. Anticancer Drugs
  12. 12. Classification  According to chemical structure and sources of drugs: ◦ Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others  According to biochemical mechanisms of anticancer action: ◦ Block nucleic acid biosynthesis ◦ Direct influence the structure and function of DNA ◦ Interfere transcription and block RNA synthesis ◦ Interfere protein synthesis and function ◦ Influence hormone homeostasis According to the cycle or phase specificity of the drug: ◦ Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents (CCSA) However – They may overall act as Cytotoxic (directly nonspecific action on cells) or at specific target or Indirectly via Hormone
  13. 13. Drugs acting directly on cells (cytotoxic drugs) Alkylating Agent: ◦ Nitrogen mustards: mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, Mephalan ◦ Ethylenimine: Thio-TEPA ◦ Alkyl sulfonate: Busulfan ◦ Nitrosoureas: Carmustine, Lomustine ◦ Triazine: Dacarbazine, Tremozolomide ◦ Methylhadrazine: Procarbazine ◦ Platinum: cis-platinium, carboplatin and Oxaliplatin Antimetabolites: ◦ Folate antagonist: Methotrexate (Mtx), Penetrexed ◦ Purine antagonist: 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) ◦ Pyrimidine antagonist: 5-Fluorouracil and cytarabine
  14. 14. Cytotoxic Drugs – contd. Antitubulins: vinca alkaloids (vincristine and vinblastin) and taxanes (paclitaxel and docetaxel), Estramustine (Bind tubulin, destroy spindle to produce mitotic arrest) Topoismerase-2 inhibitor: Etoposide Topoismerase-1 inhibitor: Topotecan and Irinotecan Antibiotic: Bleomycin, Mitomycin C, Actinomycin D (dactinomycin), Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone Miscellaneous: Hydroxyurea, L-asparginase, Tretinoin, Arsenic trioxide
  15. 15. Targetted Drugs Tyrosine protein kinase inhibitor: Imatinib, Nilotinib EGF receptor inhibitors: Geftinib, Erlotinib, Cetuximab Angiogenesis inhibitors: Bevacizumab, Sunitinib Progesterone inhibitors: Bortezomib Unnamed monoclonal antibody: Rituximab, Trastuzumab
  16. 16. Influence hormone homeostasis These drugs bind to hormone receptors to block the actions of hormones which results in inhibition of tumor growth Glucocorticoid drug: prednisolone and others Estrogens and estrogen receptor modulators: (EE, fosfestrol, SERM-tamoxifene, Toremifene) ◦ Estrogen receptor down regulators: Fulvestrant Aromatase inhibitor: Letrozole and anastrazole, Exemestane Androgen antagonists: Flutamide and Bicalutamide) Progestogen drug: Hydroxyprogesterone acetate GnRH inhibitor: Nafarelin, Triptorelin, Leuprorelin 5- reductase inhibitors:ɑ Finasteride, Dutasteride
  17. 17. Individual anticancer drugs
  18. 18. Alkylating agents Highly reactive carbonium ion intermediate – transfer alkyl group to cellular macromolecules Position 7 of guanine residues – others also (carboxyl, hydroxyl etc.) Results in cross linking/abnormal base pairing/scission of DNA strands Also cross linking of nucleic acid with proteins Radiomimetic actions – like ionizing radiation Non specific action on cell stages Some – CNS stimulant and cholinergic properties
  19. 19. Drugs PA MOA ADRs Uses Mechlorethamine Highly reactive, local vescicant - Nausea, vomiting, extravasations - sloughing HL, NHL - MOPP Cyclophosphamide No local effect – popular and wide range of action Active metabolite – aldophosphamide, phosphoramide mustard, Immunosuppressant Alopecia and cystitis (acrolein) and emetogenic Chloramphenicol retards metabolism Solid tumours Isofosfamide Congener of Cycloph – longer t1/2 - Haemorrhagic cystitis (mesna is –SH compound), lesser emetogenic Broncogenic CA, breast, testicular, bladder, head & neck, osteogenic sarcoma Clorambucil Slow acting – for lymphoid tissue, not myeloid Immunosuppressant DOC - Chronic lymphatic leukaemia, NHL and few solid tumours Mephalan BM depression, Infection, Diarrhoea, pancreatitis Multiple myeloma Busulfan For myeolid tissue, not lymphoid Hyperuricaemia, pulmonary fibrosis and skin pigmentation DOC in CML Nitrosoureas Highly lipid soluble – wide range of activity, cross BBB CNS action – nausea, vomiting, BM depression (6 weeks) …. Visceral fibrosis and renal damage Meningeal leukaemias, brain cancer Dacarbazine Activated in liver, methylates DNA Nausea, vomiting, flu like symptoms, neuropathy and myelosuppression Malignant melanoma, HL Procarbazine Not classical agent Activated in liver, methylates and depolymerizes DNA, also inhibition of nucleic acid synthesis Mutagenic and carcinogenic, Male sterility, vomiting, leucopenia, thrombocytopenia …Weak MAO inhibitor – sedation, disulfiram reaction with alcohol MOPP regimen – HL and for brain tumours
  20. 20. Platinum compounds – cisplatin, carboplatin, oxaliplatin Hydrolyzed intracellularly to a highly reactive moiety – causes cross linking of DNA (CTR1 and MRP1) N7 of guanine residues Also reacts with –SH of cytoplasm and nuclear proteins Effects resemble alkylating agents and radiation Penetrate tissues and excreted slowly unchanged in urine T1/2 = 72 hours Uses: Metastatic testicular and ovarian tumours – also in lung, bladder, esophageal, hepatic, gastric etc. solid tumours ADRs: Highly emetic, renal impairment – hydration required; also ototoxic and neurotoxic Carboplatin – 2nd generation and oxaliplatin – 3rd generation
  21. 21. Antimetabolites Folic acid Antagonists: MTX Purine Antagonists: 6MP and 6-TG Pyrimidine Antagonists: 5-FU and Cytarabine General Characteristics: Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis Myelosuppression is the dose-limiting toxicity for all drugs in this class
  22. 22. Methotrexate – Folate Antagonist MOA: ◦ The structures of MTX and folic acid are similar ◦ MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase ◦ Enters cell by Folate carrier – converts to more active polyglutamate form (FPGS) ◦ the enzyme that normally converts dietary folate to the tetrahydrofolate required for one carbon atom transfer reactions in de novo purine synthesis and amino acid interconversion ◦ Enzyme inhibition – pseudoirreversible (although 50,000 times higher affinity than normal substrate) ◦ Additionally, also inhibits thymidylate synthase – DNA synthesis inhibition – RNA and protein also suffers ◦ Low doses – bone marrow toxicity, megaloblastic anaemia; high doses – pancytopenia ◦ Mucositis, diarrhoea and desquamation and bleeding Leucovorin rescue (folinic acid rescue): ◦ Administered as a plan in MTX therapy ◦ Leucovorin (Folinic acid) is directly converted to tetrahydrofolic acid - production of DNA cellular protein in spite of presence of MTX ◦ Used to rescue bone marrow and GIT mucosal cells ◦ Permits higher doses
  23. 23. Methotrexate – contd. Kinetics: ◦ Given orally/IM /IV and also intrathecally and good oral absorption ◦ Little metabolized, excreted unchanged in urine ◦ CSF entry - intrathecal Indications: ◦ Choriocarinoma - was the first demonstration of curative chemotherapy – 15 – 30 mg/day for 5 days ◦ Maintenance of remission of Acute lymphatic leukemia in children but not good for inducing remission ◦ Tumors of head and neck, NHL, breast and bladder cancers ◦ Meningeal metastases of a wide range of tumors Resistance: Reduction of affinity of DHFR to MTX, diminished entry of MTX into cancer cells and over production of DHFR enzyme Permetrexed: Newer congener of Mtx – targets thymidylate synthase - less interference with DHFRase; hand foot syndrome
  24. 24. Purine Antagonists – 6MP, 6TG and Azathioprine (AZA) Highly effective: antineoplastic – also primarily used as immunosuppressant in Rh arthritis and organ transplantation MOA: 6-MP and 6-TG - Converted to corresponding monoribonucleotides – inhibits conversion of inosine monophosphate to adenine and guanine nucleotides …also feedback inhibition of de novo purine synthesis • Get incorporated to RNA and DNA Kinetics: AZA and -MP - Metabolized by xanthine oxidase (inhibited by allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th ◦ 6-TG is also metabolized by s- methylation ◦ 6-MP also metabolized by methylation by thiopurine methyl transferase ((TPMT) – genetic deficiency of TPMT – toxicity ◦ Over expression of TPMT – resistance to 6-MP ◦ Toxicity of Azth – enhanced due to TPMT deficiency ADRs: all cause BM depression, nausea vomiting with 6-MP, reversible jaundice and hyperuricaemia Uses: Childhood acute leukaemia, choriocarcinoma, solid tumours , both to induce remission and 6-MP to maintain Azathioprine : prodrug – converts to 6-MP (prominent immunosuppressant action)
  25. 25. Antimetabolites (Pyrimidine Antagonists) - 5 FU Pyrimidine antagoists – antineoplastic, antifungal and antipsoriatic MOA: 5- FU ◦Fluorouracil is an analogue of thymidine ◦Converted to corresponding nucleotide - 5-fluoro-2deoxy-uridine monophosphate (5- FdUMP) – forms covalent ternary complex with methyl-THFA and thymidylate synthase (TS) – irreversible inhibition of TS ◦Blocks conversion of deoxyuridilic acid to deoxythymidylic acid – failure of DNA synthesis due to noavailability of thymidylate ◦Thymidine can partially reverse 5-FU toxicity ◦2nd mechanism: 5-FU itself gets incorporated to RNA – interferes RNA synthesis ◦Concurrent administration of Leucovorin (5-FU action depends on THFA) – enhances 5-FU action ◦Cisplatin and oxaliplatin synergizes 5-FU action
  26. 26. 5 FU – contd. Kinetics: Used IV – metabolized by dihydropyrimidine dehydrogenase (DPD) – plasma half-life – 15-20 minutes ◦ Genetic deficiency of DPD – severe 5-FU toxicity ADRs: BM and GIT myelosuppression - mucositis, diarrhoea, nausea, vomiting and peripheral neuropathy Uses: Solid malignancies – especially colon, rectum, stomach, pancreas, liver, urinary bladder and Head & Neck
  27. 27. Antitubulins Vinca alkaloids (Vinca rosea or Catharanthus roseus) Taxanes – Western yew tree Binds to microtubular protein – tubulin – prevents its polymerization – cause disruption of mitotic spindle and interfere with cytoskeletal function Chromosomes fail to move apart during mitosis – metaphase arrest Binds to β-tubulin and enhances its polymerization – microtubules are stabilized and depolymerization is prevented Stability results in inhibition of normal dynamic reorganization of the microtubule network for interphase and mitoticfunction - Abnormal microtubules are formed Vincristine – remission of childhood acute lymphoblastic leukaemia Also AML, WT, HD ADR: Neuropathy and alopecia; also paralytic ileus, postural hypotension, urinary retention Paclitaxel – Metastatic ovarian and breast carcinoma – after failure of 1st line therapy Also in small cell lung cancer, esophageal adenocarcinoma etc. Myelosupression and “stocking and gloves” neuropathy Vinblastin – With other drugs in HD, Kaposi sarcoma, NHL, breast and testicular cancer
  28. 28. Topoisomerase 1 and 2 inhibitors Etoposide: Topoisomerase-2 inhibitor – causes DNA breaks by affecting DNA Topoisomerase-2 function (G2 Phase) – testicular and lung cancers Topotecan, Irinotecan: Similar to etoposide but acts on Topoisomerase – 1 – used in metastatic carcinoma of ovary and lung cancer
  29. 29. Antibiotics – Actinomycin D, Daunorubicin etc. Actinomycin D (Dactinomycin): Potent antineoplastic Highly effective in Wilm`s Tumour and chilodhood rhabdomyosarcoma Also in Mtx resistant choriocarcinoma, Ewing`s sarcoma, metastatic testicular carcinoma MOA: Blocking of RNA transcription by interfering with template function of DNA – also single strand break in DNA (dactinomycin) ADRs: Vomiting, stomatitis, diarrhoea, erythema, desquamation of skin Daunorubicin: Limited to acute myeloid and lymphoblastic leukaemia Doxorubicin: Also effective in many solid tumours – breast, lung, sarcoma, thyroid, ovary, bladder MOA: Intercalate between DNA strands – block DNA and RNA synthesis; also strand breakage of DNA Toxicity: Cardiotoxicity – arrhythmia and hypotension – ECG; also CHF Also mutagenic and carcinogenic
  30. 30. Miscellaneous Hydroxyurea: Inhibits ribonucleoside diphosphate reductase – so blocks conversion of ribonucleotides to deoxyribonucleotide (S specific action) Well absorbed orally – t1/2 – 4 hours Uses: CML, Polycythaemia vera ◦Important use: Radiosensitizer prior to radiotherapy and 1st line drug in sickle cell disease in adults ADRs: Myelosupression, GIT disturbance and cutaneous reactions
  31. 31. L-asparginase (L-ASPase) Leukaemic cells are deficient in L-aspargine synthase enzyme – takes L-aspargine from surrounding medium ◦ L-ASPase obtained from E. coli – degrades L-aspargine to L-aspartic acid – deprive leukaemic cells – cause cell death Used in Acute lymphoblastic leukaemia – for inducing remission with Mtx, prednisolone, vincristine Drawbacks: Resistance – leukaemic cells develop L-aspargine synthase + produce antibodies which can inactivate and clears the enzyme rapidly Peg-asparginase – a polyethylene glycol L-ASPase - slow and long acting ADR: atypical ADRs – due to defective protein synthesis – hyperglycaemia, raised triglycerides, liver damage, clotting defects, allergic reactions urticaria and anaphylaxis
  32. 32. General Principles of Chemotherapy of Cancer 1. Analogous with Bacterial chemotherapy – differences are ◦ Bacterial metabolism differs from host – but malignant cells not much different - Selectivity of drugs is limited – because “I may harm you” – lately - (antigens, oncogenes – CML tyrosine protein kinase gene) ◦ Microorganisms are amenable to immunological and other host mechanism; Interferon, Interleukins, TNF etc. 1. A single clonogenic malignant cell can produce progeny – kill host. All malignant cells must be killed or removed 2. Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy – 1st order kinetics – certain fractions of cells are killed 3. Drug regimens or combined cycle therapy to minute residual tumour cells after radiation or surgery – effectively palliate large tumour burden (Basis of treatment now) – combined modality 4. Complete remission should be the goal – used in maximum tolerated dose 5. Formerly one drug – now 2-5 drugs in intermittent pulses - Total tumour cell kill – recovery time for normal cells in between
  33. 33. Combination chemotherapy - synergistic Drugs which are effective when used alone Drugs with different mechanism of action Drugs with differing toxicities Drugs with different mechanism of toxicities Drugs with synergistic biochemical interactions Optimal schedule by trial and error method Kinetic scheduling: on the basis of cell cycle specificity (CCS)/non specificity (CCNS)
  34. 34. Cell Cycle and Clinical Importance • Malignant cells spend time in each phase - longest time at G1, but may vary • Many of the effective anticancer drugs exert their action on cells traversing the cell cycle - cell cycle- specific (CCS) drugs • Cell cycle-nonspecific (CCNS) drugs - sterilize tumor cells whether they are cycling or resting in the G0 compartment • CCS are more effective on cycling cells – generally in S-phase; but may be others also
  35. 35. Drugs Based on Cell Cycle CCNS: Nitrogen Mustards, Cyclphosphamide, chlorambucil, carmustine, dacarbazine, busulfan, L-asparginase, cisplatin, procarbazine and actinomycine D etc. CCS: ◦G1 – vincristine ◦S – Mtx, cytarabine, 6-thioguanine, 6-MP, 5-FU, daunorubicin, doxorubicin ◦G2 – Daunorubicin, bleomycin ◦M – Vincristine, vinblastne, paclitaxel etc.
  36. 36. Cell cycle and clinical importance – contd. CCS drugs are given in short courses (pulses) – non-cycling cells can reenter in between CCS drugs are scheduled after a course of CCNS drugs CCS – effective against hematologic malignancies and in solid tumors with large growth fraction CCNS drugs – solid tumors with low growth fraction solid tumors
  37. 37. The MOPP and Ewing`s Sarcoma Regimes in Hodgkin's
  38. 38. The Log kill Hypothesis One round of chemotherapy does not kill all the cells in a tumour – unlike antimicrobials Relationship of tumor cell number to time of diagnosis, symptoms, treatment and survival – expressed as logarithmic function (log kill) Cell kill hypothesis: actions of CCS drugs follow first order kinetics: a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells) – leukaemias and lymphomas Therefore, magnitude of a tumor cell kill is a logarithmic function: 4 log kill means reduction of tumour cells from1012 to 108
  39. 39. The Neoplastic Cell Burden – Log kill May have up to 1012 tumor cells throughout the body at the time of death 109 (100 crore) cells at the time of diagnosis Debulking – 90% done Still 10% left i.e. 109 became108 or 10 crores (log kill is 9-8 = 1) There would still be up to 8 logs of tumor cells ◦Inherent resistance to drug, Pharmacological sanctuary (CNS and testes), G(0) cycle 100,0000000 (109 ) 90% Debulked 10% remaining = 100000000 (108 ) Log kill = 109 - 108 = 1 LOG KILL 1 (ONE) IS NOT SUFFICIENT
  40. 40. The Neoplastic Cell Burden – Log kill An effective drug combination is capable of killing 99.999% tumor cells - clinical remission and symptomatic improvement (log kill 5) - Still 0.001% cells In common bacterial infections – host defense mechanism would take care However, in cancer, single clonogenic malignant cell – produce progeny kill host cells Therefore, early treatment, continuation beyond zero cell diagnosis and scheduling of these agents, 100,0000000 (109 ) 99.999% or above = 999990000 cells Remaining 0.001% = 100,0000000 – 999990000 = 10, 000
  41. 41. Approaches to Drug Treatment • DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) • LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e. kill rate > growth rate) • GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistent secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.
  42. 42. Approaches to Drug Treatment – Image from you Textbook
  43. 43. Resistance Intrinsic and Acquired Intrinsic: Some tumor types, e.g. malignant melanoma, renal cell cancer, and brain cancer, exhibit primary resistance, i.e. absence of response on the first exposure, to currently available standard agents Acquired: ◦Single drug: change in the genetic apparatus of a given tumor cell with amplification or increased expression of one or more specific genes ◦Multidrug resistance: ◦Resistance to a variety of drugs following exposure to a single variety of drug ◦increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (P- glycoprotein) involved in drug efflux
  44. 44. Toxicity countering - common ones Folinic acid rescue – Mtx (administration of > 100 fold dose of Mtx) Systemic Mesna (sodium-2-mercaptoethane sulfonate) administration and irrigation by acetylcysteine – detoxify toxic metabolites (cyclophosphamide) Vomiting: Ondansetron Amifostine (organic thiophosphate) - activation (cisplatin – nephrotoxicity)) Hyperurecaemia: uricosuric agents like allopurinol, alkalization of urine and plenty of fluid Hypercalcaemia: Multiple myeloma, breast cancer etc. IV fluid and Bisphosphonates Pulse therapy: 2 – 3 weeks intervals drug therapy Platelet and granulocyte transfusion: to prevent bleeding and infection Granulocyte colony stimulating factors (GM-CSF/G-CSF) – recovery of granulocytopenia (myelosupression)
  45. 45. Thank you