Cancer Chemotherapy: Mechanisms and Classification of Anticancer Drugs
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The document discusses various aspects of cancer chemotherapy including: 1. Guiding principles of cancer chemotherapy aim for total cell kill through early diagnosis, combination chemotherapy, and intermittent regimens. 2. Chemotherapeutic agents are classified based on their mechanism of action and cell cycle specificity, and include alkylating agents, antimetabolites, natural products, and hormones/antagonists. 3. Common chemotherapeutic drugs are discussed including their mechanisms of action, uses, and adverse effects. Chemotherapy aims to destroy cancer cells while limiting toxicity to normal cells.
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Cancer Chemotherapy: Mechanisms and Classification of Anticancer Drugs
- 1. Presented by Shaheen Begum M.Pharm, I Year I Sem Pharmacology, UCPSc, Kakatiya University. 1
- 2. • Cancer – Uncontrolled multiplication and spread within the body of abnormal forms of body's own cells • Neoplasm – A mass of tissue formed as a result of • Abnormal • Excessive • Uncoordinated • Autonomous and • purposeless Proliferation of cells 2 1
- 3. 3
- 4. Cancer cells differ from normal cells by • Uncontrolled proliferation • De-differentiation & loss of function • Invasiveness • Metastasis 4 2,3,4
- 5. Guiding principles in cancer chemotherapy • To achieve cure a TOTAL CELL KILL must be tried • Early diagnosis and early initiation of treatment • Combination chemotherapy • Intermittent regimens • Adjuvant and neoadjuvant chemotherapy occasionally 5 5,6,7
- 6. Total cell kill • Aimed at destroying all the malignant cells, leaving none • This approach ensures – Early recovery – Prevents relapse – Prolongs survival 6
- 7. Early diagnosis and early T/t why? • Survival time inversely related to initial number of cells • Aging cancer cells are less susceptible to chemotherapy, because there is – ↑ cell cycle (division) time – ↓No of actively dividing cells with more resting cells – ↑ cell death within tumor – Overcrowding of cells 7
- 8. CLASSIFICATION - I: CELL CYCLE NON SPECIFIC : Kills resting cells & dividing cells • Cyclophosphamide • Chlorambucil • Cisplatin • Actinomycin-D • L-asparaginase CELL CYCLE SPECIFIC Kills actively dividing cells • G1 – Vinblastine • S – Methotrexate 6-Mercaptopurine 5-Fluorouracil • G2 –Bleomycin Etoposide, Topotecan Daunorubicin • M – Vincristine Vinblastine Paclitaxel,Docetaxel 8 5
- 9. • Nitrogen Mustards – Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide • Ethyleneimine : Thiotepa • Alkyl Sulfonate: Busulfan • Nitrosureas – Carmustine,lomustine, streptozocin • Triazines – Dacarbazine, temozolamide Alkylating agents 9 5
- 10. • Folate Antagonists – Methotrexate • Purine Antagonists – 6 Mercaptopurine, 6 Thioguanine, Azathioprine • Pyrimidine antagonists – 5 Fluorouracil, cytarabine, gemcitabine Antimetabolites 10 5
- 11. • Antibiotics – Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitomycin C • Vinca alkaloids – Vincristine, Vinblastine, Vinorelbine • Taxanes – Paclitaxel, docetaxel • Enzymes – L-Asparginase Natural Products • Epipodophyllotoxins – etoposide, tenoposide • Camptothecin analogs – Topotecan, irinotecan • Biological response modifiers – Interferons, – Interleukins 11 5
- 12. • Cisplatin • Carboplatin • Hydroxurea • Procarbazine • Mitotane • Imatinib Miscellaneous Agents 12 5
- 13. CLASSIFICATION - II: Depending on mechanism at cell level • Directly acting cytotoxic drugs: – Alkylating agents – Antimetabolites – Natural products • Antibiotics • Vinca alkaloids • Taxanes • Epipodophyllotoxins • Camptothecin analogs • Enzymes • Biological response modifiers – Miscellaneous: Cisplatin, carboplatin • Indirectly acting- by altering the hormonal mileau : – Corticosteroids – Estrogens & ERMs – 5 alpha reductase inhibitors – Gnrh agonists – Progestins 13 5
- 14. Hormones & antagonists • Corticosteroids – Prednisolone • Estrogens – Ethinyl Estradiol • SERM – Tamoxifene, Toremifene • SERD – Fulvestrant • Aromatase Inhibitors – Letrozole, Anastrazole, Exemestane • Progestins – Hydroxyprogesterone • Anti-androgens – Flutamide, Bicalutamide • 5- reductase Inhibitors – finasteride, dutasteride • GnRH analogs – Naferelin, goserelin, leuoprolide 14 5
- 15. 15
- 16. 16
- 17. Mechanism of action Alkylating Agents Form highly reactive carbonium ion Transfer alkyl groups to nucleophilic sites on DNA bases Results in Cross linkage Abnormal base pairing DNA strand breakage ↓ cell proliferation Alkylation also damages RNA and proteins 17
- 18. • Nausea & Vomiting • Bone marrow depression • Alopecia • Gonads: Oligospermia, impotence, ↓ ovulation • Foetus: Abortion, foetal death, teratogenicity • Carcinogenicity • Hyperuricaemia • Immunosupression: Fludarabine • Hazardous to staff General toxicity of cytotoxic drugs 18
- 19. • Cytotoxic action – Hemopoetic system highly susceptible • Chlorambucil – more against lymphoid series • Busulfan – more against myeloid series – Epithelial tissues, hair follicles – Spermatogenesis , fetopathic effect • Immunosupressant action • Miscellaneous – Severe nausea & vomiting • Known as radiomimetic drugs Pharmacological actions 19
- 20. • Very irritant drug • Dose = 0.4 mg/kg single or divided • Uses – Hematological cancers , lymphomas , solid tumors – Hodgkins • Adverse effects – Anorexia, nausea, vomiting – Bone marrow depression, aplasia – Menstrual irregularities Mechlorethamine (Mustine) 20
- 21. 21
- 22. Uses of cyclophosphamide • Neoplastic conditions – Hodgkins and non hodgkins lymphoma – Neuroblastoma , retinoblastoma – breast , adenocarcinoma of ovaries • Non neoplastic conditions – Rheumatoid arthritis • Adverse effects: – Hemorrhagic cystitis, – alopecia, – nausea & vomiting, hepatic damage 22
- 23. Nitrosureas • Highly lipid soluble, Cross BBB • Uses: – Meningeal / Brain tumours • Dose :150-200 mg/m2 BSA every 6 wks (Carmustine) • Adverse Effects: – Delayed bone marrow suppression – Visceral fibrosis, renal damage 23
- 24. Triazenes • Dacarbazine – Primary inhibitory action on RNA & protein synthesis – Used in malignant melanoma • Temozolamide – New alkylating agent – Approved for malignant glioma – Rapidly absorbed after oral absorption & crosses BBB 24
- 25. Cisplatin • Non cell cycle specific killing • Administered IV • Highly bound to plasma proteins • Gets conc in kidney, intestine, testes • Poorly penetrates BBB • Slowly excreted in urine Pt NH3Cl Cl NH3 Dose: 20 mg for 5 days a week 75 – 100 mg once in 4 weeks to treat ovarian cancer 25
- 26. Mechanism of action of cisplatin Cisplatin enters cells Forms highly reactive platinum complexes DNA damage Intra strand & interstrand cross links Inhibits cell proliferation Cl- 26
- 27. Cisplatin uses and adverse effects • Uses – Testicular cancer (85% - 95 % curative ) – Ovarian cancer – Other solid tumors: lung, esophagus, gastric • Adverse effects – Emesis – Nephrotoxicity – Peripheral neuropathy – Ototoxicity 27
- 28. Methotrexate Adenine, guanine, thymidine , methionine, serine Folic acid not useful in toxicity Folinic acid N5 formyl FH4 should be given which is converted to N5,N10- Methylene –FH4 and bypasses the inhibited reductase 28
- 29. Pharmacological actions • Cytotoxic actions – Predominant on bone marrow – foetal malformations and death • Immunosupressive action • Anti-Inflammatory action 29
- 30. Uses of methotrexate • Antineoplastic – Choriocarcinoma and tropoblast tumor Immuno-supressive agent • Rheumatoid arthritis, resistant asthma,Psoriasis. • Medical termination of pregnancy • Adverse effects • Megaloblastic anemiaThrombocytopenia,leukopenia, aplasia , Oral, intestinal ulcer , diarrhoea Alopecia , liver damage. 30
- 31. 6 Mercaptopurine 6 MP 6 Thiouric acid Xanthine oxidase Allopurinol TPMT Inactive metabolite 31
- 32. • Use: – Acute leukemia (ALL) – Choriocarcinoma • Adverse Effects: – Bone marrow & GIT mainly – Hepatic necrosis rarely – Hyperuricaemia 6 Mercaptopurine 32
- 33. 5 fluorouracil 5 FU FdUMP dUMP Thymidine Monophosphate Thymidilate synthetase DNA Synthesis (Selective failure) Uses : stomach , colon, breast ovaries , liver, skin cancers FdUMP = fluorodeoxyuridine monophosphate 33
- 34. • Obtained from periwinkle plant ( Vinca Rosea) • Vincristine, vinblastine, vindesine, vinorelbine • These are microtubule damaging agents Vinca alkaloids 34
- 36. Taxanes • Paclitaxel & docetaxel • Plant product obtained from bark of Pacific Yew ( Taxus Brevifolia) & European Yew (Taxus Buccata) 36
- 37. Mechanism of action Cell cycle arrested in G2 and M phase 37
- 38. • Paclitaxel – Administered IV – Use: advanced breast & ovarian cancer also lungs, esophagus, prostrate cancer – Adverse effects: • Anaphylactoid reaction because of solvent cremaphor • Myalgia, myelosupression, peripheral neuropathy • Docetaxel – Oral – Used in refractory breast & ovarian cancer – Major toxicity neutropenia may cause arrhythmias hypotension 38
- 39. Epipodophyllotoxins • Etoposide & tenoposide • Semisynthetic derivatives of podophyllotoxins podophyllum peltatum (plant glycoside) • Act in S & G2 phase • Inhibit topoisomerase II which results in breakage of DNA strands & cell death • Uses: – Testicular tumors – cancer of lungs 39
- 40. • Derived from camptotheca accuminata • Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted • Topotecan: – Used in metastatic ovarian cancer – Major toxicity is bone marrow depression • Irinotecan – Used in metastatic cancer of colon/rectum – Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects Camptothecin analogs 40
- 41. • Cell cycle non specific drugs • Derived from streptomyces species • MOA: – Intercalation in the DNA between adjoining nucleotide pairs – blocks DNA & RNA synthesis – Generation of oxygen radicals which mediate single strand scission of DNA – Action on Topoisomerase II Anticancer antibiotics 41
- 42. • Uses: – Wilm’s tumor, – gestational chorio carcinoma • Adverse effects – bone marrow supression – Irritant like meclorethamine – sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur – Gastrointestinal adverse effects Dactinomycin 42
- 44. L-asparaginase • Isolated from E.coli • Use: Acute Lymphocytic Leukemia (ALL) • Dose : • 6000 to 10000U/kg IV daily for 3-4 weeks • A/E: • Hepatic damage • Hypersensitivity , hemorrhage • Hyperglycemia, headache, hallucinations , confusion, coma 44
- 45. Hormones & antagonists • Corticosteroids – Prednisolone • Estrogens – Ethinyl Estradiol • SERM – Tamoxifene, Toremifene • SERD – Fulvestrant • Aromatase Inhibitors – Letrozole, Anastrazole, Exemestane • Progestins – Hydroxyprogesterone • Anti-androgens – Flutamide, Bicalutamide • 5- reductase Inhibitors – finasteride, dutasteride • GnRH analogs – Naferelin, goserelin, leuoprolide 45
- 46. Glucocorticoids • Marked lympholytic effect so used in acute leukaemias & lymphomas, • They also – Have Anti-inflammatory effect – Increase appetite, prevent anemia – Produce sense of well being – Increase body weight – Supress hypersensitivity reaction – Control hypercalcemia & bleeding – Non specific antipyretic effect – Increase antiemetic effect of ondansetron 46
- 47. Estrogens • Physiological antagonists of androgens • Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer • Fofesterol – Prodrug , phosphate derivative of stilbesterol – 600-1200mg IV initially later 120-240 mg orally 47
- 48. • Tamoxifen : Non steroidal antiestrogen Selective Estrogen Receptor Modulators (SERMs) Agonistic: Uterus, bone, liver, pitutary Antagonistic: Breast and blood vessels 48
- 49. Tamoxifen • DOSE:10-20mg bd • Standard hormonal treatment in breast cancer • Adverse effects: – Hot flushes , vomiting, vaginal bleeding, menstrual irregularities, venous thromboembolism, dermatitis, rarely endometrial cancer 49
- 50. • Pure estrogen antagonist • USES: Metastatic ER+ Breast Ca in postmenopausal women • MOA: • Inhibits ER dimerization & prevents interaction of ER with DNA • ER is down regulated resulting in more complete supression of ER responsive gene function Selective Estrogen Receptor Down regulator (fulvestrant) 50
- 51. • Letrozole • Orally active non steroidal compound • MOA : Inhibits aromatisation of testosterone & androstenedione to form estrogen. • Uses : Breast Ca- & adj. to mastectomy • Dose :2.5mg bd orally • Anastrozole : more potent • 1mg OD in ER+ Breast Ca • A/E : hot flushes Aromatase Inhibitors 51
- 52. • FLUTAMIDE & BICALUTAMIDE : • Androgen Receptor antagonists • Dose : 250 mg tds, 50mg od resp. • Palliative effect in metastatic Prostatic Ca after orchidectomy Anti androgens 52
- 53. 5- reductase inhibitors Finasteride • Orally active • DHT levels ↓ • Benign prostatic hyperplasia Dose: 5mg/day Prostate volume Symptom score Peak urine flow rate DHT level in prostate Side effects: Loss of libido & impotence in 5 % pts. Also used for prevention of hair loss 53
- 54. • NAFERELIN : nasal spray / SC inj • ↓FSH & LH release from pituitary- ↓ the release of estrogen & testosterone • USE : Breast Cancer, Prostatic Cancer • PROGESTINS: • Hydroxyprogesterone – used in metastatic endometrial Cancer. • A/E: bleeding GnRH agonists 54
- 55. 55
- 56. Newer anticancer drugs • Inhibitors of growth factors receptors – Imatinib: CML (BCR-ABL gene) – Gefitinib: Non small cell cancer of lungs (EGFR) – Nilotinib : CML (Tyrosine kinase inhibitor) – Dasatinib : CML (Tyrosine kinase inhibitor) – Lapatinib : metastatic breast cancer (HER2/neu) – Sunitinib : renal cell carcinoma (VEGF) – Sorafinib : renal cell carcinoma (VEGF) 56 9
- 57. • Monoclonal antibodies – Trastuzumab : breast cancer (HER2/neu) – Bevacizumab: metastatic colon cancer (VEGF) – Rituximab : non hodgkins lymphoma (CD-20) – Panitumumab : metastatic colon cancer (EGFR) – Alemtuzumab : CLL (CD 52 antigen) – Iodine tositumonab : Non hodgkins (CD-20) Newer anticancer drugs7 57
- 58. References 1. Rang and Dale 5th edition ppt:693 Elsevier Publication. 2. Favoni RE 2000 - The Role of Polypeptide growth factors in human carcinomas, Pharmacol Rev 52: 179-206. 3. Workman P, Kaye 2002- New Potential Approaches to the development of anticancer drugs, Mol Med Suppl8: 1-73. 4. Weinberg R A 1996, Senderowicz A M 2000- how cancer arises, Cell Cycle Control J Natl Cancer Inst 92: 376-387 5. Essentials of Medical Phrmacology 7th Edition- ppt:858 Jaypee Brothers Medical Publishers (P) LTD. New Delhi. 6. Talapatra S, Thompson C B -2001 Growth factor signaling in cell survival. J Pharmacol Exp Ther 298: 873-878 7. Sikic B I 1999- New Approaches in Cancer Treatment. Ann Oncol 10 : S149-S153 (Coverage of Monoclonal Antibodies) 58
- 59. 8. Batchelor TA, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell, 2007, 11:83–95. 9. Sequist LV, Lynch TJ. EGFR tyrosine kinase inhibitors in lung cancer: An evolving story. Annu Rev Med, 2008, 59:429–442. 10. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med, 2001, 344:783–792. 11. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol, 2006, 8:448–457 12. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J, 2001, 1:65–70. 59
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Editor's Notes
- Overcrowding of cells: poor blood supply and nutrition and defective access of drugs
- All alkylating agents have alkyl groups and they can transfer this alkyl group to suitable receptor site. Alkylating agents in neutral or alkaline solution form highly reactive carbonium ion which is quaternary ammonium derivative(The carbon atom has only six electrons in its outer space so highly reactive). This carbonium ion is highly reactive and can react with groups like NH2, SH, OH or PO4 in physiologically important molecules in cell and render them unavailable for normal metabolic reactions. One more property of this carbonium ion is its nucleophilicity it can react with nucleic acid bases and inhibit DNA synthesis . The nitogen at guanine position 7 is especially more susceptible. So this results in cross linking inhibits DNA replication . Abnormal base pairing (alkylated guanine pairs with thymine instead of cytosine) results in production of defective protein DNA strands breakage – decreased cell proliferation Alkylation also damages RNA and proteins Non cycle specific
- Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells
- Common to the alkylating agents Cytotoxic action in general damage nuclei of growing multiplying cells, hemopoetic system highly susceptible to this action leads to anemia, thrombocytopenia, leukopenia and in toxic doses bonemarrow supression., Net result similar mode of action may differ chlorambucil more effective against lymphoid series and busulfan more effective against myeloid series. These drugs also effect epithelial tissues like cornea, intestinal mucosa leading to desquamation and ulcers Hair follicles- alopecia’sprematogenesis, foetopathy sand ammenorrhoea Immunosupressant action : supress antibody production Miscellaneous: nausea, vomiting Radiomimetic drugs: actions resemble that of biological or ionizing radiations, all alkylating agents different radiomimetic action.
- First nitrogen mustard to be used in cancer chemotherapy Very irritant drug: vesicant for skin, eyes, resp tract , should be given only IV , Special care sloughing can occur with extravasation Available as 10 mg HCL with 90 mg NACL should be reconstituted in 10 ml NS or distilled water and given immediately because it becomes active in few minutes Hodkins stage III and stage IV as a part of MOPP mechlor, oncovin (Vincristine), procarbazine, prednisolone Chronic myelogenous leukemia, chronic lymphoblastic leulemia Because of serious toxicity use replaced by less toxic drugs carmustine Estramustine: stable combination of estrogen & mustine designed to deliver mustine to estrogen receptor site of tumor like prostrate cancer Advantage: both cytostatic and hormonal effect
- Wegeners granulomatosis
- Streptozocin indicated for T/t of islet cell carcinoma of pancreas 500mg/m2 for 5 days or 1000 mg/m2 weekly
- Heavy metal complex has water soluble planar coordination complex containing central platinium atom surrounded by 2 cl and 2 NH3
- Nephrotoxicity can be reduced by hydration of patients and diuresis by litres of normal saline and mannitol, Hyperuricaemia can occur Neuropathy : large sensory fibres – numbness, tinglingfollowed by loss of joint position and disabling sensory ataxia Ototoxicity : tinnitus and hearing loss in high frequency range , more pronounce in children Rarely shock mutagenic, teratogenic , carcinogenic adverse events reversible on stoppage
- One of most commonly used anticancer agents Cell cycle specific drug acts in S phase Methotrexate has antineoplastic, immunosuoressant and anti-inflammatory action It produced the first striking although temporary remission of leukemia and first cure for choriocarcinoma Mechanism of action of methotrexate: methotrexate structurally resembles folic acid , it competitively inhibits dihydrofolate reductase enzyme and blocks conversion of DHFA to THFA THFA is an essential coenzyme required for one carbon transfer reactions in denovo purine synthesis and synthesis of thymidilate , amino acid conversions which are required for DNA SYNTHESIS it also inhibits RNA and protein synthesis. More toxic to rapidly dividing cells like bone marrow
- Choriocarcinoma and trophoblast tumor in women RHEUMATOID ARTHRITIS :5-7.5MG PER WEEK ORALLY FOR 8 WEEKS PSORIASIS 2.5-5MG AT 12HRLY INTERVALS WEEKLY Also used in mycosis fungoides , Some role in AML and non hodgkins lymphoma MTP: 25 TO 50 MG ORAL THEN 3-7 DAYS LATER misoprostol 800 microgram vaginally in early part of forst trimester < 8 weeks of gestation
- Well absorbed orally, metabolized rapidly by xanthine oxidase, use of xanthine oxidase inhibitor allopurinol decreases the inactivation of 6 MP, xanthine oxidase also required in uric acid synthesis, so allopurinol may be used in cancer chemotherapy to reduce dose of 6 MP and also decrease the hyperuricaemia 6 MP ALSO METABOLISED BY METHYLATION IN PRESENCE OF ENZYME THIOPURINE METHYL TRANSFERASE, GENTIC DEFICIENCY OF THIS ENZYME MAKES INDIVIDUAL MORE SUSCEPTIBLE TO 6 MP toxicity , while over expression is important method of resistance. Azathiprine is also substrate for xanthine oxidase but 6 thiguanine is not.
- Hyperuricaemia occurs due to massive destruction of cells of lymphoid series , urine should be maintained alkaline and its volume adequate. Other purine analogs like 6 thioguanine and azathiprine also posses cytotoxic actions how ever they do not have any advantage over 6 mercaptopurine as antileukemic agents Mercaptopurine with azathiprine decrease the dose by ¼ to ½ Azathiprine: Imuran Used as immunosupressive agent in organ transplantation and autoimmune conditons like hemolytic anemia, glomerulonephritis, and rhe umatoid arthritis
- 5 fluoro uracil is converted in body to corresponding nucleotide fluorodeoxyuridine monophosphate, Fluorinated analog of pyrimidine acts by inhibiting thymidilate synthesis Also gets incorporated into DNA in place of uracil Uses: topically intreatment of premalignant keratosis Even resting cells are more affected though rapidly multipling cells are more susceptible Toxic to bone marrow , alimentary epitheliumand CNS Administered by slow IV infusion to prevent first pass metabolism.
- Vc and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation Resistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.
- Taxanes bind to beta tubulin subunits of microtubules at a site different from binding site of vinca alkaloids, colchicine, podophyllotoxin, unlike vinca alkaloids they promote polymerization of microtubules & inhibit depolymerization, leading to stabilization of polymerized microtubules and arrests cells in mitosis and eventually leads to activation of apoptosis The stabilization of microtubules is damaging to cells because of disturbances in in the dynamics of various microtubule dependent structures that are required for functions like mitosis, maintainence of cellular morphology, locomotion and secretion.
- Dexamethasone, h1 antagonists supress the reaction Abraxane: Albumin bound form of paclitaxel no anaphylactoid reaction
- Topoisomerase I modulates supercoiling of DNA by complexing with it and nicking one of its strands
- Intercalation in the DNA: The drugs insert nonspecifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis. Intercalation can interfere with the topoisomerase II–catalyzed breakage/reunion reaction of supercoiled DNA strands, causing irreparable breaks. Generation of oxygen radicals: Cytochrome P450 reductase (present in cell nuclear membranes) catalyzes reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA (Figure 39.18). Tissues with ample superoxide dismutase or glutathione peroxidase activity are protected.10 Tumors and heart tissue are generally low in SOD. In addition, cardiac tissue lacks catalase and, thus, cannot effectively scavenge hydrogen peroxide. Lipid peroxidation therefore may explain the cardiotoxicity of anthracyclines.
- Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA,8 forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals. Adverse effects: The major dose-limiting toxicity is bone marrow depression. The drug is immunosuppressive. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur.
- CLINICAL RESPONSE TO L-ASPARGINASE IS DISAPPOINTING, THOUGH REMISSIONINDUCED IN ACUTE LEUKEMIA IS SHORT LASTING , IT IS NOW USED WHEN OTHER DRUGS HAVE FAILED , INEFFECTIVE IN SOLID TUMORS
- Prevent anemia: prevent acceletated erythrocytic destruction, They effectively counter hemolytic and hemorrhagic complications accompanying chronic lymphocytic and malignant lymphomas, Prednisolone is generally started in doses of 60 – 100 mg daily in divided doses and then depending on response reduced to maintenance dose of 20 -40 mg /day The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and decreased lymphoid mass. [Note: At high doses, cortisol is also lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes.] Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas. Glucocorticoids have some secondary role in hormone responsive breast cancers, they are also valuable for treatment of complications like treatment of hypercalcemia, hemolytic anemias, thrombocytopenia, incresed intracranial tension, mediastinal edema occuring after radiotherapy, they afford symptomatic relief by mood elevating and antipyretic effects and also adjuvants of antiemetics. Useful in treating cerebral edemas due to intracranial cerebral metastasis
- Fosfesterol is activated to slibesterol in prostatic tissue and acheives high conc in prostatic tissue thus it is used in prostrate cancer Adverse effects – impotence and gynaecomastia
- SERMS are non steroidal synthetic agents whose agonist or antagonist action on estrogen receptors are tissue selective, produces beneficial estrogenic actions in some tissues (bone, brain, liver), and prevent certain deleterious effect in breast and endometrium by exhibiting antagonistic or no action on ER Tamoxifen: Non steroidal antiestrogen related structuraly to slilbesterol, given orally it competes with the circulating estrogen for cytoplasmic estrogen receptor binding site, the metabolites of tamoxifen have much stronger affinity for receptors and are not easily displaced by circulating estradiol. At low concentration they have cytostatic effect on ER positive cells, higher conc cause cytotoxic effect . Because of antagonistic action in breast DOC in treatment of ca breast in ER+ AS WELL as some ER- breast cancer also male breast
- Well absorbed orally, biphasic half life 10 hrs and also 7 days, and long duration ofaction some metabolites of tamoxifen are more potent antiestrogens, the drug is excreted primarily in bile. Other SERMS- raloxifene – no risk of endometrial carcinoma, used as first line drug in treatment of postmenopausal osteoporosis, toremifene – new congener of tamoxifen with similar actions uses and adverse effects ORMELOXIFENE – dub, acts as antagonist in breast and uterus
- USES: Metastatic ER+ Breast Ca in postmenopausal women which has stopped responding to tamoxifen Higher affinity for ER probably accounts for efficacy in tamoxifen resistant cases
- Aromatization of A ring of testesterone and androstenedione is final and key step in production of estrogens estradiol and estrone in body, in addition to circulating hormone the locally produced hormone may play an important role in breast cancer development, exemestane also aromatase inhibitor