CYTOSTATICS Martínková, 2005

1. CYTOSTATICS Martínková, 2005

2. Action - toxicity Most drugs used in cytostatic chemotherapy interfere with the synthesis of DNA and /or RNA, with the results that cell death occurs or cell multiplication ceases. These effects are not confined to malignant cells- most cytostatic agents are also toxic to normal dividing cells, particularly those in bone marrow, the GIT, gonads, hair follicles and skin.

3. General principles in the use: cytostatics interfere with several different stages of the cell cycle and so open the way to the rational use of drug combinations. Cycle non-specific drugs act at all stages in the proliferating cell cycle (but not in the G0 resting phase) Phase-specific drugsact only at a specific phase :the more rapid the cell turnover the more effective they are.

4. The cell cycle and the phase specificity of some cytotoxic drugs. G0 = resting phase G1 = prereplicative phase G2 = postoperative phase S = DNA synthesis M = mitosis or cell division

6. Adjuvant therapy: • courses of cytostatic drugs are given when the cancer has apparently been destroyed by surgery or radiotherapy. • Its objective is to eradicate micrometastases. • Neoadjuvant therapy: • is defined as a preoperative cytostatic treatment, • in patients with locally advanced solid tumors; • the aims of neoadjuvant chemotherapy + radiotherapy are: • the potentiality of curative resection, • the reduction of surgical measures, and • an increase in life span.

8. Can we decrease toxicity? Bone marrow suppression and autologous stem cell support

9. Dose-response/toxicity curves demonstrating the potential therapeutic benefit of autologous stem cell support. (Kuhlmann 1996) Increase in therapeutic effect

10. RESISTANCE • primary: (non-responsive tumors) • aquired: • reduced uptake of drugs • deletion of enzyme to activate drug • increased detoxication of drug • increased concentration of target enzyme • rapid repair of drug-induced lesion • decreased number of receptors for drug • increased efflux

11. Mechanisms of cellular drug resistance  deletion of enzyme to activate drug  increased detoxication of drug  reduced uptake of drugs  inactivated cytotoxic drug active metabolite C  increased efflux (multidrug resistance) defective cellular target T rapid repair of drug-induced lesion +T increased concentration of target molecules T- cellular target +T - gene amplification

12. 1. ALKYLATING AGENTS • 2.ANTIMETABOLITES • a. folic acid antagonists-MTX • b. pyrimidine antagonists - 5 FU, ara-C • c. purine antagonists - 6-MP, 6-TG

13. 3. PLANT ALKALOIDS: etoposide, Vinca alkaloids, paclitaxel 4. ANTIBIOTICS : doxorubicin, daunorubicin, bleomycin 5. HORMONES: estrogens, aminoglutethimide, progestogens, glucocorticosteroids 6. PLATINUM COMPOUNDS:cisplatin,carboplatin 7. MISCELLANEOUS AGENTS: procarbazine 8. INTERFERONS:

14. 1. A L K Y L A T I N G AGENTS:cyclophosphamide, • ifosphamide, chlorambucil, nitrosoureas • cycle-nonspecific drugs • combine with DNA of both malignant and normal cells and • thus damage not only malignant cells but also dividing normal • cells (the bone marrow and the GIT) • mechanisms: the alkyl groupings (ethyleneimine ions and • positively charged carbonium ions) are highly reactive, so that • combine with susceptible groups in cells and in tissue fluids • (SH, PO4) •  The alkylating action on DNA leads to abnormal base • pairing or intra and interstrand links with DNA molecule • cytotoxic, mutagenic and teratogenic effects may result • from interaction swith DNA

16. Cyclophosphamide • an inactive prodrug • can be given orally  is activated by the CYP450 in liver as well as in tumors.  with time, the active metabolite and also acrolein are formed. The latter compound is responsible for bladder toxicity (chemical hemorrhagic cystitis).  a wide spectrum antitumor and immunosuppressive activity  used as a part of combination therapy regimens to treat lymphoma, breast cancer, bladder cancer, ovarian cancer and various children malignancies

17. T o x i c i t i e s:  bone marrow depression, granulocytopenia, thrombocytopenia.  urotoxicity appears with chronic therapy - M e s n a … dimesna (2-mercaptoethane sulfonate sodium) protects the urinary tract against the irritant effects by supplying sulfhydryl groups to form a stable thioether with acrolein. Mesna is given by IV injection or by mouth The nitrosoureas:carmustine and lomustine are potent bone marrow toxins. Hepatotoxicity and nephrotoxicity. Broad spectrum of activity (solid tumors, in particular brain tumors).

18. 2. A N T I M E T A B O L I T E S • are structural analogues of cellular metabolites • their selectivity for malignant cells is only partial. • usually phase specific as their action is confined to • specific steps in the synthesis of nuclear material. • a. F o l i c a c i d antagonists (antifolates) • Methotrexate (MTX) is a congener of folic acid (FA). • FA is required in the synthesis of thymidylate and purine • nucleotides ( DNA). • Mechanisms: MTX competes with FA for the active site • of dihydrofolate reductase (DHFR) and thymidylate • synthetase (TS). By blocking this step, MTX prevents • nucleic acid synthesis and causes cell death.

19. 24-h IV infusion of HDMTX Prognosis: Css pl, CLtotMTX Toxicity: high-risk CssMTX end co-variates: AUCMTX , low urine pH, emesis 2 target Css for malignant cells 1 infusion • Toxicity: • high risk Css pl • iniciation and continuation • of LV rescue 3 Estimation of anindividualized dose based on CL estimates using 1and 6hCpl (Wall 2000, Evans, Relling 1994,1998) leucovorin MTX critical plasma concentration for normal cells critical duration of exposure of normal cells

21. Pharmacokinetics: MTX is reasonablyabsorbed when administered by mouth in low dosage. (When doses exceed 30 mg, progressively less of the drug is absorbed) Metabolic transformation:  intracellularly in the form of polyglutamates (n=1-7) MTX selectivity (cells capable of this conversion e.g. lymphoblasts may be expected to be more susceptible to cell kill by this drug).  in the liver the significant amount of the drug (7-30%) is metabolized by hydroxylation at the 7 position (7-OH MTX). MTX is excreted primarily unchanged by the kidney.Thus patients with renal impairment should not be treated with MTX because of the prolonged blood levels that may lead to increased hematological and gastrointestinal toxicity.

22. Dosage: MTX is used in several different regimens:  low dose (LDMTX) up to 50 mg/m2/week antiinflammatory and immunosuppresive action (psoriasis) orally, s.c.  intermediate dose < 1 g/m2 (malignancy) IV  high dose (HDMTX) > 1 g/m2(malignancy) IV Intrathecal administration is needed to prevent relapse due to malignant cells hidden after biological barriers ( blood-brain barrier, testes, eyes).

23. Antagonist: folinic acid (leucovorin)- rescue Adverse effects and toxicity: nauzea and vomiting, diarrhea stomatitis myelosuppresion renal dysfunction seizures (especially after intrathecal administration). Less common toxic effects are skin rash, pleuritis and hepatitis. Acute renal failure can be caused by tubular obstruction by crystals of MTX.  Diuresis (> 3 l/day) with alkalinization of the urine (pH :7-7.5 ) by IV administration of sodium bicarbonate reduces the incidence of nephrotoxicity.

24. Usage: LDMTX is indicated in severe psoriasis (immunosuppressant), asthma, rheumatic polyarthritis, and maintaining treatment of acute lymphoblastic leukemia (ALL). This treatment does not require folinic acid rescue. Intermediate and particularly HDMTX are used in malignancy. HDMTX in the inicial phase of ALL protocol, lymphomas and some solid tumors including osteogenic sarcoma.

26. b. P y r i m i d i n e antagonists 5 - fluorouracil  active metabolite of 5-FU that inhibits DNA synthesis through potent inhibition of thymidylate synthase is 5-fluorodeoxyuridin MP (5-FdUMP)  modulation of 5-FU action: FdUMP forms the ternary complex with an excess folate coenzyme and thymidylate synthase. For this reason a stable folate precurzor leucovorin is used followed by 5-FU treatment (colon cancer). Pharmacokinetics: 5-FU is absorbed erratically after oral administration and, therefore, is administered IV. Toxicity:leukopenia and thrombocytopenia, GIT toxicity. Stomatitis and diarrhea usually occurs 4-7 days after treatment.

27. Therapeutic uses: several solid tumors, most notably colon cancer,breast cancer, and head and neck cancers. 5-FU is metabolized in the liver. Then this drug can be administered also into the hepatic artery. This method achieves high local concentrations, with decreased systemic toxicity and is used to treat isolated hepatic metastases from colon cancer.

28. Cytosine arabinoside (ara-C) is an analog of deoxycytidine  inhibits DNA polymerase or is incorporated into DNA.  is used IV as a pulze dose or a continuous infusion. Toxicity: myelosuppresion, neurological, GIT and liver toxicity (the dose-related) Usage:the drug of choice for the treatment of acute myelocytic leukemia (AML).

29. c. Purine antagonists. 6-mercaptopurine (6-MP) and 6-thioquanine (6-TG) are converted to nucleotides intracellularly and block synthesis of purines. They are administered orally and used in the treatment of ALL. Azathioprineis a prodrug giving 6-MP (a potent immunsupressive agent).

30. Metabolická konverze 6-merkaptopurinu methylmercaptopurine methylthioinosine- e monophosphate TPMT TPMT nucleotide nucleotide 6-mercaptopurine mercaptopurine thioguanine: HPRT (thioinosine- (thioguanosine monophosphate) monophosphate thioxantosine monophosphate XO inhibition DNA thioxantine thiourine acid bioactivation

31. 3. PLANT ALKALOIDS Podophyllotoxins Vinca alkaloids- Paclitaxel Podophyllotoxins(from mandrake or May apple) - etoposideincreases degradation of DNA (similar to that seen after irradiation), possibly via stabilisating the DNA- topoisomerase II complex. It is administered IV or orally. Etoposide is very active in leukemias, testicular cancer, lymphomas and Hodgkin´s disease. Indications: hematological neoplasms (leukemias, lymphomas).

32. Vinca alkaloids-vinblastine andvincristine • bind to tubulin, a protein that forms the microtubules • that are essential for the formation of the spindle • that separates the chromosomes during mitosis- • "spindle poisons". •  low oral bioavailability (given IV). • Toxicity: • Vinblastine : leukopenia. • Vincristine :neurotoxicity • paresthesia of the fingers • and lower extremities - • profound weakness of motor strenght • (of dorsiflexing the foot and extensors of the wrists) - • obstipation and paralytic ileus

33. Usage: vinblastine - treatment of testicular cancer and Hodgkin´s disease vincristine - breast cancer, lymphomas, acute lymphoblastic leukemia

34. Paclitaxel is spindle poison This drug is most useful in ovarian cancer and in advanced breast cancer.

35. 4. ANTIBIOTICS Anthracyclinesdoxorubicin, daunorubicin. There are three main mechanisms of action:  intercalation between adjacent base pairs in DNA, thus inhibiting further nucleic acid synthesis and leading to fragmentation of DNA and inhibition of DNA repair.  membrane binding alters membrane function. This alters sodium and calcium concentrations seen in myocardium and could be involved in the development of cardiomyopathy.  free radical formation ( cardiotoxicity).

36. Toxicity:Cardiotoxicity acute and chronic A c u t e toxicity: shortly after administration with the develop- ment of various arrhythmias, that are occasionally life-threatening. Ch r o n i c toxicity: Cardiomyopathyoccurs leading to death in up to 60% of those who develop signs of congestive cardiac failure. The role of dexrazoxane. Bone marrow suppression Alopecia Extravasation causing severe tissue necrosis. Doxorubicin and daunorubicin are given IV.Vd of doxorubicin is very large. Its hepatic extraction is high with 40% appearing in bile. Dose reduction is recommended in liver disease. Daunorubicin penetrates tissues less effectively. Indications:acute leukemia, lymphomas, sarcomas and a wide range of carcinomas.

37. Bleomycin is a mixture of several polypeptide antibiotics It prevents thymidine incorporation into DNA. Adverse effects: transient fever mouth ulceration in high doses pulmonary diffuse interstitial fibrosis which can be fatal. Alopecia This antibiotic is given IV or i.m Bleomycin is used in lymphomas, testicular carcinoma, and various squamous cell carcinomas

38. 5. HORMONES and antagonists H. can cause remission in certain types of cancer (breast and prostate). Ways in which hormones can affect malignant cells:  a direct cytotoxic action on the malignant cells. This is likely if cancer cells that are normally dependent on a specific hormone are exposed to a high concentration of a hormone with the opposite effect (if a carcinoma arises from cells of the prostate that are testosterone dependent, ….estrogens in large doses are cytotoxic to the cancer)  a hormone may suppress production of the hormones by a feedback mechanism. S e x h o r m o n e s: Estrogensare used in the management of prostatic and breast carcinoma

39. Progestogens:megesteron, medroxy-progesteron acetate: adenocarcinoma of the body of the uterus and in advanced breast cancer, carcinoma of the kidney. G l u c o c o r t i c o s t e r o i d s are cytotoxic to lymphoid cells and are used with combination with other cytotoxic agents in treating lymphomas, myeloma and to induce a remission inacute lymphoblastic leukemia.

40. H o r m o n e a n t a g o n i s t s: • Anti-estrogens: • tamoxifen - in breast tissue • competes with endogenous estrogens for • the estrogen receptors and inhibits the transcription of • estrogen-responsive genes. • T. is remarkably effective in some cases of • hormone-dependent breast cancer • Anti-androgens: • flutamideis usedin prostate tumors • Adrenal hormone synthesis inhibitors:inhibit • sex hormone synthesis. Aminoglutethimide.

41. Aminoglutethimide  inhibits adrenal synthesis of estrogens, glucocorticoids and mineralocorticoids by inhibition of the enzyme producing their common precursor- pregnandione inhibits tissue aromatase blocking conversion of androgens to estrogens. Ovarian aromatase is resistant to this inhibition, so aminoglutethimide is only useful in postmenopausal women.

42. Pharmacokinetics: polymorphic acetylation to an inactive N-acetyl metabolite. Fast acetylators - slow acetylators. Adverse effects: dizziness, lethargy are common on starting treatment but decline during chronic dosing (probably due to enzyme induction). Usage: A. is effective in about 30% of postmenopausal patients with best effects on skin and breast disease. The response of bone metastases is also good.

43. 6. PLATINUM COMPOUNDS Cisplatin (cis-diaminedichlorplatinum) is an inorganic platinum complex.  mechanism of action:DNA synthesis by formation of intra-and interstrand cross-links with DNA molecule. Adverse effects, toxicity:  severe vomiting nephrotoxicity is dose-related (acute distal tubular necrosis). Prevention: the patients is fully hydrated by IV infusion combined with manitol and furosemide.  hypomagnesemia  ototoxicity develops in up to 30%. Peripheral neuropathy can be disabling.  myelosuppression

44. Cisplatin is the most effective single agent in testicular teratomas, but is usually given in combination with other cytotoxic drugs. C. has been used with some succes in head and neck and bladder cancers -IV . Carboplatin is less toxic (renaltoxicity or ototoxicity), neuropathy is rare and vomiting although common, is less severe than after cisplatin. Oxaliplatin

45. 7. M I S C E L L A N E O U S AGENTS Procarbazine depresses DNA synthesis. Its main use is in treating Hodgkin´s disease. 8. I N T E R F E R O N S hairy cell leukemia, lowgrade non-Hodgkin´s lymphoma, chronic myeloid leukemia.