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Anticancer drugs
This document discusses various aspects of anticancer drugs and chemotherapy, including: 1. Types of chemotherapy drugs like alkylating agents, antimetabolites, antibiotics, and their mechanisms of action and cell cycle effects. 2. Goals and principles of cancer therapy like cure, remission, combination chemotherapy, and developing resistance. 3. Toxicities of chemotherapy drugs and methods to counter them, like growth factors and protective agents. 4. Targeted therapies like monoclonal antibodies and tyrosine kinase inhibitors used to treat specific cancers.
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Anticancer drugs
- 1. Anticancer Drugs ? Dr.lokendraSharma Professor of Pharmacology
- 2. Treatment options ofcancer:? • No Treatment: Before 1940 • Surgery: before 1955 • Radiotherapy: 1955~1965 • Chemotherapy: after 1965 • Immunotherapy and Gene therapy
- 3. Cell Cycle ? CellCycle Specific Agents • Antimetabolites • Bleomycin • Podophyllin Alkaloids • Plant Alkaloids Cell Cycle Non-Specific Agents • Alkylating Agents • Antibiotics •Cisplatin • Nitrosoureas
- 4. Chemotherapy Cell cycle effectsof anticancer drugs ? CCS Drugs CCS Drugs CCNS Drugs G1 - S Etoposide Platinum compounds S Antimetabolites Alkylating agents G2 – M Bleomycin Etoposide (Ref Harrison 17th /525) Anthracyclines Dactinomycin M Vinca alkaloids Taxanes Ixabepilone Estramustine Mitomycin Camptothecins
- 5. Goals of Therapy? Cure or induce prolonged ‘remission’ Macroscopic and microscopic features of the cancer disappear Acute Lymphoblastic Leukaemia Wilm`s tumor, Ewing`s sarcoma etc. In children, Hodgekin`s lymphoma, testicular teratoma and choriocarcinoma
- 6. Goals of TherapyPalliation: ? Shrinkage of evident tumour, Alleviation symptoms ,prolongation of life Breast cancer, ovarian cancer, endometrial carcinoma, CLL, CML, Small cell cancer of lung and Non-Hodgekin lymphoma
- 7. Goals of Therapy? Insensitive less sensitive but life may be prolonged Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer
- 8. Aim of Therapy: Adjuvant therapy For mopping up of residual cancer cells including metastases after Surgery, Radiation and immunotherapy etc. Routinely used now Mainly in solid tumours
- 9. General Principles Analogouswith Bacterial chemotherapy – differences are Selectivity > drugs > limited No or less defence mechanism – Cytokines adjuvant now All malignant cells > killed >stop progemy Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy
- 10. General Principles Drugregimens or combined cycle therapy after radiation or surgery Complete remission should be the goal Formerly single drug – now 2-5 drugs in intermittent pulses Total tumour cell kill – COMBINATION CHEMOTHERAPY
- 11. COMBINATION CHEMOTHERAPY SYNERGISTIC ? Drugswhich are effective when used alone Different mechanism of action Differing toxicities Different mechanism of toxicities Synergistic biochemical interactions Optimal schedule by trial and error method More importantly on cell cycle specificity
- 12. Classification ? According tochemical structure and sources of drugs – Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others According to biochemistry 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)
- 13. Some Alkylating Agentsused in cancer Chemotherapy Agent Route of Admin. Cancer where preferred Delayed Toxicity 1. Busulphan Oral CML, PV BMD, bleeding, skin pigmentation adrenal insufficiency, pulmonary fibrosis 2. chlorambucil Oral CLL, PV BMD, bleeding 3. Cyclophosphamid Oral, i.v All, NHL, PV, Carcinoid tumour, Neurobalstoma BMD, bleeding, hemorrhagic, cystitis 4. Melphalan Oral Multiple myeloma BMD, Bleeding 5. Mechlorethamine i.v. Hodgkin’s disease BMD, alopecia, Diarrhea oral ulcer leukaemia 6. Cisplatin i.v. CA tests, ovary, cervix, lung, head & neck, thyroid, Melanoma Renal damage, ototoxicity, neuropathy, BMD 7. Dacarbazine i.v. Melanoma, Hodgkin’s disease BMD 8. Carmustine (BCNU) i.v. Brain tumors Leucopenia, thrombocytopenia 9. Lomustine (CCNU) Oral Brain tumors Leucopenia, thrombocytopenia 10. Thiotepa i.v. CA bladder (early) & Ovary BMD
- 14. Some antimetabolites usedin cancer chemotherapy Agent Route of admin. Cancer (s) where preferred Delayed toxicity Cytarabine i.v. AML BMD, nausea, Vomiting stomatitis ataxia (cerebrallar) 5- Fluorouracil i.v. Carcinoma head & neck, Stomach colon, breast BMD, Oral and GI ulceration, nausea, diarrhea, neurotoxicity, *hand and foot syndrome 6- Mercaptopuine Oral All BMD, Hyperuricaemia, immunosuppression, hepatotoxicity Methotrexate Oral All, choriocarcinoma, osteogenic sarcoma BMD, vomiting, oral & GI ulcers hepatotoxicity (acute & chronic) Thioguanine Oral AML BMD, Hyperuricaemia
- 15. Block nucleic acid(DNA, RNA) biosynthesis Antimetabolites: • Folic Acid Antagonist: inhibit dihydrofolate reductase (methotrexate) • Pyrimidine Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine) • Purine Antagonist: inhibit interconversion of purine nucleotide (6-mercaptopurine and 6-Thioguanine) • Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea)
- 16. Structure & Functionof DNA Alkylating Agent: Mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, Mephalan, Busulfan, Nitrosoureas and Thio-TEPA Platinum: Cis-platinium, carboplatin and imatinib Antibiotic: Bleomycin and mitomycin C Topoismerase inhibitor: camptothecin analogues and podophyllotoxin and antibiotics like actinomycin D, daunorubicin and doxorubicin
- 17. Sites of AntineoplasticAction ? PALA = N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.
- 18. Clinical Considerations ? Early intensive start …. helpful Complete remission….. goal Combined chemotherapy useful …..delayed emergence of resistance Combined chemotherapy …..curative Treatment must continue past the time when cancer cells can be detected using conventional techniques
- 19. Resistance ? Intrinsic: malignantmelanoma, renal cell cancer, and brain cancer, exhibit primary resistance Acquired: Single drug: change in the genetic apparatus amplification or increased expression of one or more specific genes Multidrug resistance: Resistance variety of drugs 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
- 20. Toxicities ? Harmful tonormal tissues too Steep dose response curve Low therapeutic index Particularly harmful to rapidly multiplying normal tissues: GI mucosa, Bone Marrow, RE system and gonads and hair cells Effects are in dose dependent manner
- 21. Toxicities ? Bonemarrow depression – limits treatment Buccal mucosa erosion – high epithelial turnover (stomatitis, bleeding gums) GIT: Diarrhoea, shedding of mucosa, haemorrhage Nausea, vomiting – CTZ direct stimulation Skin: alopecia Gonads: oligospermia, impotence, amenorrhoea and infertility Lymphoreticular system: Lymphocytopenia and inhibition of lymphocyte function – loss of host defense mechanism – susceptibility to infections Carcinogenicity Teratogenicity and Hyperuricemia
- 22. Distinctive Toxicities ofAlkylating Agents ? Drug Toxicity Cyclophosphamide Alopecia, Hemorrhage cystitis, SIADH Ifosfamide Hemorrhagic cystitis, SIADH Busulfan Pulmonary fibrosis, Hyper pigmentation, Adrenal insufficiency Procarbazine Secondary leukemias, Disulfiram like reaction, behavioral changes, CNS depression Cisplatin Emesis, Nephrotoxicity, Peripheral sensory neuropathy, ototoxicity
- 23. Countering the Toxicities? Intermittent therapy Folinic acid rescue Systemic Mesna (sodium-2-mercaptoethane sulfonate) administration and irrigation by acetylcysteine – detoxify toxic metabolites Ondansetron Hyperurecaemia: uricosuric agents like allopurinol Platelet and granulocyte transfusion Granulocyte colony stimulating factors (GM-CSF/G- CSF) – recovery of garnulocytopenia
- 24. Drugs used toprevent toxicity of Anti cancer drugs Drug Mechanism Indications Allopurinol Inhibit xanthine oxidase Prevent hyperuricemia from tumor lysis syndrome Rasburicase Recombinant urate oxidase Prevent hyperuricemia from lysis Mesna Neutralizing agent Prevent hemorrhagic cystitis due to ifosfamide and high dose cyclophosphamide Leucovoring Replete Tetrahydrofolic acid Rescue after high dose methotrexate Amifostine Prevent radiation induced xerostomia and Prevent radiation induced xerostomia and cisplatin induced nephrotoxicity Dexrazoxane Iron chelator Prevent cardiotoxicity due to anthracyclines Palifermin Keratinocyte growth factor Prevent mucositis following chemotherapy Pilocarpine Cholinergic agonist Radiation induced xerostomia Pamidronate and Zolendronate Bisphosphonates Hypercalcemia of malignancy
- 25. Drugs used toprevent toxicity of Anti cancer drugs Drug Mechanism Indications Epoetin alpha and darbopoetin alpha Erythropoietin Anemia Filgrastim, peg- filgrastim G-CSF and Febrile neutropenia prophylaxis Sargramostim GM - CHF Oprelvekin IL-11 Thrombocytopenia Ondansetron 5-HT3 antagonist Nausea and vomiting Granisetron Palonosetron Aprepitant NK – 1 antagonist Cisplatin induced delayed vomiting
- 26. Interfere Protein Synthesis Antitubulin: vinca alkaloids (vincristine and vinblastin) and taxanes (paclitaxel and docetaxel) Bind tubulin, destroy spindle to produce mitotic arrest Influence amino acid supply: L-asparaginase .
- 27. Tyrosine Kinase Inhibitors DrugInhibit TK activated Indication Axitinib VEGFR – 1,2,3 Advanced renal cell carcinoma Bosutinib Abl –bcr, src CML Crizotinib c-MET, ALK Non small cell lung carcinoma Cabozantinib c-MET, VEGFR-2 Medullary carcinoma thyroid Dasatinib abl -bcr CML Erlotinib EGFR Non small cell lung carcinoma Pancreatic carcinoma Geftinib abl-bcr, c- KIT, PDGF Non small cell lung carcinoma Imatinib her-2/neu, erb-B2 CML GIST Lapatinib abl-bcr Breast carcinoma Nilotinib VEGFR-1,2,3 PDGFR α β c-KIT CML Pazopanib abl-bcr Advanced renal cell carcinoma
- 28. Tyrosine Kinase Inhibitors DrugInhibit TK activated Indication Regorafenib VDGFR2, TIE2 Colorectal carcinoma GIST Ruxolitinib JAK 1,2 Myelofibrosis Sorafenib VEGFR, PDGFR RAF Renal cell carcinoma Hepatocellular carcinoma Sunitinib VEGFR, PDGFR c- KIT, FLT-3 RET Renal cell carcinoma, Pancreatic neuroendocrine tumors GIST Tofacitinib JAK Rheumatoid arthritis Vandetanib VEGFR, EGFR Medullary carcinoma thyroid Vemurafenib BRAF Maliganant melaonma
- 30. Monoclonal Antibodies S. No. Monoclonal antibodyTargeted against Indication Comments 1 Rituximab CD - 20 Non hodgkin lymphoma 2 Alemtuzumab CD - 52 Low grade lymphomas and CLL 3 Trastuzumab HER 2/neu Breast Carcinoma Can cause cardiotoxicity 4 Cetuximab and panitumumab EGFR EGFR – positive metastatic colorectal carcinoma Cause rash, Hypomagnesemia and tnterstitial lung disease 5 Bevacizumab VEGF Metastatic colorectal carcinoma Combined with 5 - FU 6 Gemtuzumab CD-33 CD-33 Positive AML Linked to calicheamicin 7 I131 – Tositumomab Y90 – Ibritumomab tiuxetan CD-20 Relapsed lymphomas Conjugated with radioisotopes 8 Denileukin diftitox - Recurrentcutaneous T-cell lymphoma Recombinant IL – 2 plus diphtheria toxin
- 31. Therapy of choicefor various cancers S. No. Diagnosis Treatment of choice 1 ALL Induction: Vincristine + Prednisolone+Daunorubicin+ Asparaginase+Intrathecal Methotrexate Consolidation: Hyper-CVAD alternated with cytarabine+Methotrexate 2 AML Cytarabine+Daunorubicin/Idarubicin 3 CML Imatinib 4 CLL FCR or Fludarabine 5 Hairy cell leukemia Cladribine 6 Hodgkin disease ABVD 7 Non hodgkin lymphoma CHOP-R 8 Multiple Myeloma Bortezomib+Dexamethasone+Lenalidomide 9 Waldenstrom macroglobulinemia FCR(Fludarabine,Cyclophosphamide,Rituximab) 10 Polycthemia vera Hydroxyurea
- 32. Therapy of choicefor various cancers S. No. Diagnosis Treatment of choice 11 Non small cell lung cancer Cisplatin + Vinorelbine ± Bevacizumab 12 Small cell lung cancer Cisplatin + Etoposide 13 Mesothelioma Cisplatin + Pemetrexed 14 Head and neck cancer Cisplatin + 5-FU
- 33. Cancer Chemotherapy Agent Cancer(s) where preferred Delayed toxicity Antibiotics 1. Bleomycin Carcinoma testis, malignant effusion (intracavity) Alopecia, oedema of hand, pulomonary fibrosis, stomatitis 2. Dactinomycin Wilm’s tumour Alopecia, BMD, Stomatitis, Oral ulcer 3. Daunorubicin AML Alopecia, BMD, Cardiomyopathy 4. Doxorubicin HL, NHL, neuroblastoma, Carcinoma thyroid, stomach, carcinoid tumouir, sarcomas, osteogenic sarcoma Alopecia, BMD, Cardiomyopathy, stomatitis 5. Mitomycin Carcinoma stomach Thrombocytopaenia, leukopaenia 6. Streptozotocin (sreptozocin) Insulinoma Renal damage, hypoglycaemia, hyperglycaemia, liver damage, BMD, fever eosinophilia, nephrogenic diabetes insipidus
- 34. Some natural productsin cancer chemotherapy Agent Cancer (s) where preferred Delayed toxicity Plant Alkaloids 1. Docetaxel Advance case of carcinoma breast Neurotoxicity, fluid retention, neutropaenia 2. Etoposide Carcinoma testis, choriocarcinoma Alopecia, BMD 3. Paclitaxel Carcinoma breast, ovary BMD, peripheral neuritis 4. Vinblastine HD Alopecia, BMD, Loss of reflex 5. Vincristine ALL, NHL Alopecia, BMD, Peripheral neuritis 6. Vinorelbine Carcinoma lung BMD, fatigue, constipation, hyporeflexia paresthesia
- 35. Miscellaneous agents includingmonoclonal antibodies in cancer chemotherapy Agent Route of admin. Cancer(s) where used Delayed toxicity 1. Asparaginase i.v. ALL in child Hepatotoxicity, mental depression, pancreatitis 2. Cisplatin i.v. CA testis, ovary, cervix, lung, head & neck, thyroid, melanoma Renal damage, otoxicity neuropathy, BMD 3. Hydroxyurea Oral CML, AML (blast crisis) BMD 4. Mitotane Oral Adrenocortical carcinoma Adrenal insufficiency, diarrhea, lethargy, skin rash (transient) 5. Mitoxantrone Oral AML BMD, cardiotoxicity, alopecia 6. Imatinib Oral CML (chronic phase) & blast crisis Fluid retention (periorbital and ankle oedema), diarrhoea, myalgia 7. Trastuzumab i.v. Carcinoma breast (metaastatic) BMD, cardiomyopathy, pulm. Toxicity, cardiac failure
- 36. Hormones, their antagonistsand related agents in cancer chemotherapy Agent Route of admin Cancer(s) where preferred Delayed toxicity Corticosteroids Hydrocortisone Prednisone Oral Oral All, CLL, NHL, HL Multiple myeloma Fluid retention, Hypertension, diabetes mellitus, susceptibility to infection, moon face Androgens Testosterone i.m. Premenopausal breast cancer (oestrogen receptor positive) Fluid retention masculinization Oestrogens Diethylstilboesterol Ethinyloestradiol Oral Oral Carcinoma prostate, Postmenopausal breast cancer (oestrogen receptors negative) Feminization, Fluid retention Progestins Hydroxyprogesterone Medroxyprogesterone i.m. Oral Carcinoma endometrium None
- 37. Influence hormone homeostasis Estrogensand estrogen antagonistic drug (EE, SERM-tamoxifene) Androgens and androgen antagonistic drug (flutamide and bicalutamide) Progestogen drug (hydroxyprogesterone) Glucocorticoid drug (prednisolone and others) Gonadotropin-releasing hormone inhibitor: nafarelin, triptorelin aromatase inhibitor: Letrozole and anastrazole
- 38. Hormones, their antagonistsand related agents in cancer chemotherapy Agent Route of admin Cancer(s) where preferred Delayed toxicity Antiandrogen Flutamide Oral Carcinoma prostate None Antiandrogen Tamoxifen Oral Carcinoma breast (early stage, metastatic after surgery) None Others GnRH Agonist Goserelin Leuprolide s.c) s.c.) Carcinoma prostate None Aromatase Inibitors Aminogulutethimide Oral Metastatic breast cancer None Peptide hormone Inhibitor s.c. Carcinoid tumour None
- 39. Choice of drugin some malignancies where the response of chemotherapy is very good Cancer Treatment of choice 1. Acute lymphocytic leukaemia Induction: Vincristine + presnisone Maintenance: Methotrexate + Mercaptopurine + Cyclophosphamide 2. Hodgkin’s disease stage I and II Stage III and IV Radiotherapy Doxorubicin + bleomycin+vinblastine+dacarbazine 3. Non Hodgkin’s disease Cyclophosphamide + doxorubicin + vincristine + prednisolone 4. Choriocarcinoma Methotrexate + folic acid or cisplatin + etoposide 5. Cancer testis Bleomycin + cisplatin+ etoposide 6. Wilm’s tumour Surgery + radiotherapy followed by vincristine + dactinomycin
- 40. Choice of drugin some malignancies where the response of chemotherapy is good Cancer Treatment of choice 1. Acute myeloid leukaemia Cytarabine + idarubicin/daunorubicin 2. Chronic lymphocytic leukaemia Chlorambucil + prednisone (if indicated) + fludarabine or cytarabine alone or in combination with other drugs 3. Chronic myelogenous leukaemia Busulfan or interferon, imatinib (bone marrow transplatation in selected patients) 4. Multiple myeloma Melphalan + prednisone 5. * Carcinoma breast stage 1 Tomoxifen after breast surgery 6. Endometrial carcinoma Progestins or tamoxifen 7. Carcinoma cervix Radiation + cisplatin (localized), cisplatin/carboplatin (metastatic) 8. Carcinoma prostate GnRh agonist or oestrogen + androgen anatagonist (flutamide)
- 41. Choice of drugin some malignancies where the response of chemotherapy is average Cancer Treatment of choice 1. Carcinoma breast stage II to IV Cyclophosphamide + methotrexate + 5-FU or Transtuzumab + prednisone + antioestrogen 2. Carcinoma ovary Cisplatin or carboplatin + paclitaxel + interferom 3. Carcinoma thyroid Radioidine (I131 ), doxorubicin, cisplatin 4. Carcinoma stomach 5-FU + doxorubicin + mitomycin 5. Carcinoma colon 5-FU + leucovorin + irinotecan 6. Osteogenic sarcoma Doxorubicin or methotrexate with leucovorin after surgery 7. Melanoma Dacarbazine, cisplatin, interferon
- 42. Choice of drugin some malignancies where the response of chemotherapy in unsatisfactory Cancer Treatment of choice 1. Carcinoma lung Etopise + cisplatin, vinorelbine 2. Carcinoma head and neck 5-fu+cisplatin or cisplatin + paclitaxel 3. Carcinoma adrenal gland Mitotane 4. Carcinoid tumour Doxorubicin + cyclophospamide or 5- FU + octreotide 5. Polycythaemia vera Busulfan, chlorambucil or cyclophospamide
- 44. Alkylating Agents Mechanism ofAction: • Nitrogen mustards inhibit cell reproduction binding irreversibly nucleic acids (DNA) • After alkylation, DNA is unable to replicate • no synthesize proteins and essential cell metabolites • Consequently, cell reproduction inhibited cell eventually dies inability maintain metabolic functions.
- 45.
- 46. Subgroups of AlkylatingAgents • 1) Nitrogen mustards • 2) Nitrosoureas • 3) Alkyl sulfonates • 4) 4-Platinum Coordination Compounds 1-Nitrogen Mustards E.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil a-Mechlorethamine - first alkylating agent employed clinically - bifunctional, thus can crosslink DNA - extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV. Clinical Uses -Hodgkin’s Disease -Non-Hodgkin’s Lymphoma Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression
- 47. Nitrogen Mustards • Mechlorethamine: –Uses: IV – MOPP (Mechlorethamine – oncovine-prednisolone and procarbazine) in Hodgekin`s lymphoma and disease – ADRs: Severe Vomiting, myelo and immunosuppression – Extravasation – severe local toxicity • Cycolphosphamide: – Transformed active aldophosphamide and phospharamide – orally – Used Hodgkin's lymphoma, breast and ovary cancers – Ifosphamide longer half life and used mainly testicular tumour
- 48. Nitrogen Mustards –contd. • Chlorambucil: orally, active against lymphoid tissues (Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma) • Busulfan: orally, active against CML • Carmustine: IV, effective against brain tumors and Hodgkin's lymphoma • Dacarbazine: Different from other alkylating agents – action against RNA and protein synthesis – Used Melanoma and Hodgkin's lymphoma
- 49. Antimetabolites Folic acid Antagonists:MTX Purine Antagonists: 6MP and 6TG Pyrimidine Antagonists: 5FU and cytarabine General Characteristics: Antimetabolites S phase-specific drugs structural analogues of essential metabolites and that interfere with DNA synthesis. Myelosuppression dose-limiting toxicity
- 50. Methotrexate – FolateAntagonist • MOA: – Structures MTX and folic acid similar – MTX actively transported mammalian cells and inhibits dihydrofolate reductase – the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis • Leucovorin rescue: – Administered as a plan in MTX therapy – Leucovorin (Folinic acid) is directly converted to tetrahydrofolic acid - production of DNA cellular protein inspite of presence of MTX – Used to rescue bone marrow and GIT mucosal cells
- 51. Methotrexate – contd. •Kinetics: – orally/IM /IV intrathecally , good oral absorption – CSF entry - intrathecal • Indications: – Choriocarinoma - was the first demonstration of curative chemotherapy – Tumors of head and neck – Breast cancer – Acue lymphatic leukemia – Meningeal metastases of a wide range of tumors
- 52. Purine Antagonists –6MP, 6TG 6-Mercapapurine (6-MP) and others • Exact mechanisms uncertain – inhibit purine base synthesis • Used in childhood Acute lymphatic Leukaemia for maintenance and remission • combination MTX choriocarcinoma • Metabolized xanthine oxidase (inhibited by allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th • Well tolerated, mild myelosuppression , hepatotoxicity on long term administration
- 53. Antimetabolites (Pyrimidine Antagonists)- 5 FU • MOA: – Fluorouracil analogue of thymine – Converted to 5-fluoro-2deoxy-uridine monophosphate (5-FdUMP) – 5-FdUMP inhibits thymidylate synthase and blocks conversion of deoxyuridilic acid to deoxythymidylic acid – failure of DNA synthesis • Indications: solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck
- 54. Antibiotics • Anthracyclines (doxorubicinand dau norubicin), Dactinomycin, Bleomycin, and mitomycin • Anthracyclines: – Enters themselves into DNA and causes DNA break – Activates TopoisomeraseII and cause break in DNA strands – Generates excess free radicals causing production of superoxide – damage to DNA – Known to damage cardiac cells also (unique) – Resistance developes due to increased eflux of drug – Uses: Doxo- Breast, ovary, lung, [prostate and acute lymphatic leukaemia – Dauno- ALL and AML
- 55. 2-Nitrosoureas • - bifunctional •- active against broad spectrum of neoplastic disease • - inhibits synthesis of both DNA and RNA, as well as proteins • - These drugs are highly lipophilic, so they can easily cross blood-brain-barrier, and are great for CNS tumors. • - Big problem in this class is that they are highly mutagenic and highly carcinogenic. • - Major toxicity is DELAYED bone marrow depression & Pulmonary fibrosis. Clinical uses - primary and metastasis tumors of the brain - Hodgkin’s Disease - Non-Hodgkin’s lymphoma - Adenocarcinoma of stomach, colon, and rectal cancer - Hepatocarcinoma E.G.: a-Carmustine b-Lomustine
- 56. 3-Alkyl Sulfonates Busulfan Clinical uses Greateffect on for Chronic granulocytic Leukemia Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression. - Pulmonary infiltrates and pulmonary fibrosis - Tonic-clonic seizures in epileptics
- 57. 4-Platinum Coordination Compounds E.G.: Cisplatin •forms crosslinks within DNA strands. Clinical Uses - Very powerful against TESTICULAR CANCER - Also good for carcinomas of ovary, bladder, head, and neck Toxicity/ Side Effects - Renal tubular damage (minimized via massive hydration coupled with anti- emetics) - Ototoxicity and peripheral neuropathy - VERY SEVER vomiting( Ondanosetron…?) Carboplatin: is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.
- 58. 3-Etoposide • podophyllotoxin, atoxin found in the mandrake root. • An inhibitor of the enzyme topoisomerase II. cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying. Then the cells die. Side effect • Vomiting & alopecia • Bone marrow suppression uses • It has been useful for treatment of testicular cancer and small cell lung cancer.
- 59.
Editor's Notes
- #4 CellCycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent) Cycling cells are more sensitive
- #10 Analogous with Bacterial chemotherapy – differences are Selectivity of drugs is limited – because “I may harm you” No or less defence mechanism – Cytokines adjuvant now All malignant cells must be killed to stop progemy – surival time is related to no. of cells that escape Chemo attack Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy
- #11 4.Drug regimens or combined cycle therapy after radiation or surgery (Basis of treatment now in large tumour burdens) 5.Complete remission should be the goal – but already used in maximum tolerated dose – so early treatment with intensive regimens 6. Formerly single drug – now 2-5 drugs in intermittent pulses – Total tumour cell kill – COMBINATION CHEMOTHERAPY
- #13 According to chemical structure and sources of drugs Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others According to biochemistry 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)
- #16 Thymidylate synthase: Deoxyuridilic acid to deo0xythymidylic acid – direct failure of DNA synthesis. Cytarabine – blocks generation of cytidylic acid
- #19 Early intensive start to the treatment is helpful Complete remission is the goal of chemotherapy Combined chemotherapy is useful - Drug regimens or effective designing of number of cycles can reduce large tumour burden and delayed emergence of resistance Combined chemotherapy can be curative when applied to minute residual tumour cell population after surgery or radiation Treatment must continue past the time when cancer cells can be detected using conventional techniques
- #20 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
- #38 These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth Estrogens and estrogen antagonistic drug (EE, SERM-tamoxifene) Androgens and androgen antagonistic drug (flutamide and bicalutamide) Progestogen drug (hydroxyprogesterone) Glucocorticoid drug (prednisolone and others) Gonadotropin-releasing hormone inhibitor: nafarelin, triptorelin aromatase inhibitor: Letrozole and anastrazole
- #45 Mechanism of Action: Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA) The specific type of chemical bonding involved is alkylation After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.
- #47 Subgroups of Alkylating Agents 1) Nitrogen mustards 2) Nitrosoureas 3) Alkyl sulfonates 4) 4-Platinum Coordination Compounds 1-Nitrogen Mustards E.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil a-Mechlorethamine - first alkylating agent employed clinically - bifunctional, thus can crosslink DNA - extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV. Clinical Uses -Hodgkin’s Disease -Non-Hodgkin’s Lymphoma Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression - Nausea/ Vomiting- Alopecia - Diarrhea - Sterility
- #48 Mechlorethamine: Uses: IV MOPP (Mechlorethamine – oncovine-prednisolone and procarbazine) in Hodgekin`s lymphoma and disease ADRs: Severe Vomiting, myelo and immunosuppression Extravasation – severe local toxicity Cycolphosphamide: Transformed active aldophosphamide and phospharamide Administered orally Used in Hodgkin's lymphoma, breast and ovary cancers Ifosphamide has longer half life and used mainly I n testicular tumour
- #49 Chlorambucil: given orally, active against lymphoid tissues (Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma) Busulfan: given orally, active against CML Carmustine: given IV, effective against brain tumors and also in Hodgkin's lymphoma Dacarbazine: Different from other alkylating agents – action against RNA and protein synthesis Used against Melanoma and Hodgkin's lymphoma
- #50 Folic acid Antagonists: MTX Purine Antagonists: 6MP and 6TG Pyrimidine Antagonists: 5FU 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
- #51 MOA: The structures of MTX and folic acid are similar MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis Leucovorin rescue: Administered as a plan in MTX therapy Leucovorin (Folinic acid) is directly converted to tetrahydrofolic acid - production of DNA cellular protein inspite of presence of MTX Used to rescue bone marrow and GIT mucosal cells Resistance: Reduction of affinity of DHFR to MTX Diminished entry of MTX into cancer cells Over production of DHFR enzyme
- #52 Kinetics: Given orally/IM /IV and also intrathecally and good oral absorption CSF entry - intrathecal Indications: Choriocarinoma - was the first demonstration of curative chemotherapy Tumors of head and neck Breast cancer Acue lymphatic leukemia Meningeal metastases of a wide range of tumors ADRs: 1) Myelosuppression - severe leukopenia, bone marrow aplasia, and thrombocytopenia 2) GIT disturbances 3) renal toxicity (crystalluria)
- #53 6-Mercapapurine (6-MP) and others Exact mechanisms of action are still uncertain – inhibit purine base synthesis Used in childhood Acute lymphatic Leukaemia for maintenance and remission and may also be in combination with MTX in choriocarcinoma Metabolized by xanthine oxidase (inhibited by allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th Well tolerated, mild myelosuppression and hepatotoxicity on long term administration
- #54 MOA: Fluorouracil is an analogue of thymine Converted to 5-fluoro-2deoxy-uridine monophosphate (5-FdUMP) 5-FdUMP inhibits thymidylate synthase and blocks conversion of deoxyuridilic acid to deoxythymidylic acid – failure of DNA synthesis Indications: solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck ADRs: nausea and vomiting, myelosuppression, and oral and gastrointestinal ulceration. Nausea and vomitting are usually mild Mucosal damage and myelosuppression
- #56 b-Cyclophsphamid -It acts as cytotoxic and immunosuppressor agent. - Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen mustard. - bifunctional agent -most widely used alkylating agent Clinical Uses - Hodgkin’s Disease - Non-Hodgkin’s lymphoma - Solid tumors of head, neck, ovaries, and breast - frequently used in combination with methotrexate (anti-metabolite) or doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post breast cancer surgery - Organ transplant recipients (due to immunosuppressive actions) Toxicity/ Side Effects - bone marrow depression - severe nausea and vomiting - acute hemorrhagic cystitis and renal damage???? (can be minimized via high fluid intake/infusion and the use of………?) - sterility - hypersensitivity reactions
- #58 3-Alkyl Sulfonates Busulfan Clinical uses Great effect on for Chronic granulocytic Leukemia Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression. - Pulmonary infiltrates and pulmonary fibrosis - Tonic-clonic seizures in epileptics - Nausea and vomiting - Alopecia - Sterility - Skin hyper pigmentation - Cataracts - Hepatitis
- #59 4-Platinum Coordination Compounds E.G.: Cisplatin forms crosslinks within DNA strands. Cis-platin is not really an “alkylating” agent, but since it operates via the same mechanism as the alkylating agents, it is placed within that group. Clinical Uses - Very powerful against TESTICULAR CANCER - Also good for carcinomas of ovary, bladder, head, and neck Toxicity/ Side Effects - Renal tubular damage (minimized via massive hydration coupled with anti-emetics) - Ototoxicity and peripheral neuropathy - VERY SEVER vomiting( Ondanosetron…?) Carboplatin: is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.
- #60 3-Etoposide Chemically it is deriven from podophyllotoxin, a toxin found in the mandrake root. An inhibitor of the enzyme topoisomerase II. cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying. Then the cells die. Side effect Vomiting & alopecia Bone marrow suppression uses It has been useful for treatment of testicular cancer and small cell lung cancer.