Anticancer agents_Undergraduate class KIU.pptx

Fish Management

1. Anticancer agents Dr. Sarah Nanzigu Makerere University College of Health Sciences All C hemical Agents that act against Neoplasia

2. Outline Relevant Background- Cancer development Cancer Chemotherapy Classification of anticancer agents Classes based on mechanism of action Antimetabolites Alkylating agents Topoisomerase Inhibitors Antitumor antibiotics Hormone antagonists Mitotic inhibitors Plant alkaloids Targted therapies Immunotherapies Other agents with anticancer activity General mechanisms of resistance to anticancer agents

3. BACKGROUND

4. Cancer Development Cancer development follows changes in the growth control mechanisms of normal cells (often genetic/ chromosomal changes) These changes eventually lead to development and reproduction of abnormal cells (cancerous cells) Cancer cells may eventually metastasize to other organs via the circulatory and lymphatic systems There are some recorgnizable agents that are pro-cancer (Carcinogenic agents) Therefore, management may include: Removing/killing abnormal cells (Drugs/Surgery/Radiation) Interfering with changes in growth control Attempts against the carcinogenic agent s

5. Some of the recorgnized Carcinogenic Agents Chemical Carcinogens Physical Agents Ionizing Radiation Oncogenic Viruses 80 - 90% of all cancers may be related to environmental agents including diets, lifestyles, and viruses. Several environmental agents often act together (co-carcinogenesis).

6. Cancer primarily results when the normal cellular genes become dysregulated such that they are inappropriately activated. T he dysregulation may follow Point Mutations The ras gene is an oncogene that becomes activated by a point mutation. Chromosomal Translocations Translocation of chromosome 9 and 22 in CML creating a fusion gene that produces an activated tyrosine kinase . Gene Amplification Specific oncogenes such as N-myc and C-neu are amplified in neuroblastoma and breast cancer respectively.

7. Cell Division and Cancer Developement G0 = Resting or differentiation phase G1 or first Gap phase = Synthesis of cellular components for DNA synthesis. The cell grows and prepares to replicate its DNA S, or synthesis phase = Replication of DNA Genome G2, or second gap phase = Synthesis of Cellular components for mitosis The cell prepares to divide itself M, or mitosis phase = Entire C ell division occurs Cell division cycle occurs in phases Replication of its DNA (S phase) Replication of other cellular componemts (M phase) Rests in between (Gaps) to allow synthesis and verifying the components ahead of replication Control mechanisms to ensure harzard replication and use of unfit cellular components in replication

8. Details of controlled cell division As a cell approaches the end of G1 phase, it is controlled at a vital checkpoint, G1/S, where the cell determines whether to replicate its DNA or not . The cell is checked for DNA damage to ensure that it has all the necessary cellular machinery needed for successful cell division. Cells with intact DNA continue to S phase; cells with unrepairable damaged DNA are arrested and commit suicide through apoptosis. A second checkpoint occurs at the G2 phase between the synthesis of DNA in S phase but before cell division in M phase. When functioning properly, cell cycle regulatory proteins act as the body's tumor suppressors by controlling cell growth and inducing the death of damaged cells. Genetic mutations causing malfunction/ absence of one/ more regulatory proteins at checkpoints can cause "molecular switch", permitting uncontrolled cell multiplication.

9. Tumor Suppressor Genes A class of genes that normally suppress cell proliferation . Examples are p53 and Rb . Mutations that inactivate the tumor suppressor gene products can release cells from growth suppression and lead to hyperproliferation. Basically: A shift in control mechanisms that govern cell proliferation and differentiation Excessive proliferation: Formation of local tumours (compress or invade) or cell migration Cells have some chromosomal abnormalities but retain ability to undergo repeated proliferation cycles

10. CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Evidence of contact inhibition Intermittent / coordinated growth facto r secretion Oncogene expression is rare Presence of tumor suppressor genes Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells Normal cell Few mitoses Cancer Cells and Normal Cells

11. Treatment of Cancer Surgery to remove solid tumors Radiation to kill cancer cells that have spread to adjacent local or regional tissues Chemotherapy to kill cancer cells located throughout the body Use of chemical agents (Antineoplastics) to destroy cancer cells Alas! Antineoplastic drugs cannot differentiate between normal and cancerous cells - Hence side effects

12. CANCER CHEMOTHERAPY Biochemic mechanisms utilized by anticancer agents 1) Interfere nucleotide synthesis. 2) Impact the structure and function of DNA 3) Interfere with transcription and block RNA synthesis. 4) Interfere with protein synthesis and functions. 5) Change hormone lever.

13. CLASSIFICATION OF ANTICANCER AGENTS Basing on specificity of target of the cell divison cycle Cell-cycle Specific (CCS) drugs - Act at specific phase of the cell division cycle - Cell cycle Non Specific (CCNS) drugs Preferably kill proliferating cells; Act on cells at all phases. Classification basing on mechanism of action Alkylating agents-Alkylate the DNA and intefere with its replication Antimetabolites- Inhibit the synthesis of folic acid, purines, pyrimidines Topoisomerase Inhibitors - Intefere with DNA unwinding Antitumor antibiotics Hormone antagonists Mitotic inhibitors The list is long- See next section Usually both classifications are required to understand how the mechanism of action influences the drug target

14. Chemotherapy against cancer cells CELL CYCLE SPECIFIC DRUGS (CCS ) Primary action during specific phases of cycle CELL CYCLE NON-SPECIFIC DRUGS (CCNS ) Acts during any phase, including G Plant alkaloids ( G 2 -M Phases) Disrupt microtubule function Vinca alkaloids: vinblastine, vincristine, vinorelbine Taxanes : paclitaxel and docetaxel Epothilones: ixabepilone Estramustine Mitotic Inhibitors (often plant alkaloids) Act in M phase but can damage cells in all phases For cancers of breast, lung, myelomas, lymphomas, leukemias Alkylating Agents crosslinking agents Alkylates and Damage the DNA Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, melphalan and mechlorethamine Nitrosoureas: streptozocin, carmustine, lomustine Alkyl sulfonates: busulfan Triazines : dacarbazine (DTIC) and temozolomide Ethylenimines : thiotepa and altretamine Platinum Based: Cisplatin, oxaliplatin , and carboplatin Treat leukemia, lymphoma, Hodgkin disease, multiple myeloma, sarcoma, cancers of lung, breast, ovary The ability to kill cancer cells depends on its ability to halt cell division

15. Chemotherapy against cancer cells CELL CYCLE SPECIFIC DRUGS (CCS ) Primary action during specific phases of cycle CELL CYCLE NON-SPECIFIC DRUGS (CCNS ) Acts during any phase, including G DNA synthesis inhibitors ( S Phase) Antimetabolites: 5-fluorouracil (5-FU), Methotrexate, 6-mercaptopurine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Pemetrexed, Pentostatin, Thioguanine Antitumor antibiotics Anthracycline antibiotics Interfere with enzymes involved in DNA replication Daunorubicin, Doxorubicin, Epirubicin, Idarubicin Other Antitumor Antibiotics: Actinomycin -D, Mitomycin -C, and bleomycin Topoisomerase Inhibitors Interfere with enzymes (topoisomerases) which help separate the strands of DNA so they can be copied Topoisomerase I inhibitors: Topotecan and irinotecan Topoisomerase II inhibitors: Etoposide and teniposide. Mitoxantrone is similar to Doxorubicin but also inhibits topoisomerase II The ability to kill cancer cells depends on its ability to halt cell division

16. Other anticancer agents Targeted Therapies ( attack cancer cells more specifically). Most attack cells with certain mutant genes, or cells that express too many copies of a particular gene. imatinib, gefitinib, sunitinib and bortezomib Differentiating Agents : Make cancer cells to mature into normal cells; Ex retinoids, tretinoin, bexarotene, arsenic trioxide Hormone therapy: C hange the action or production of hormones needed for growth of certain cancer cells The anti-estrogens: fulvestrant, tamoxifen, and toremifene Aromatase inhibitors: anastrozole, exemestane, and letrozole Progestins :megestrol acetate Anti-androgens: bicalutamide, flutamide, and nilutamide Agonist and Analogs of GnRH, or LHRH : leuprolide and goserelin They are used to slow the growth of breast, prostate, and endometrial cancers

17. Classes based on mechanism of action Classification basing on mechanism of action regardless of cell-cycle specificity or drug orign

18. 1. Alkylating agents: chlorambucil, mechlorethamine, cyclophosphamide, melphalan 2. Antimetabolites: methotrexate, pemetrexed, 6-mercaptopurine, 5-fluorouracil, capecitabine, cytosine arabinoside, gemcytabine 3. Mitotic inhibitors: vinblastine, vincristine, paclitaxel, docetaxel 4. Antibiotics: actinomycin D, doxorubicin, daunomycin, bleomycin 5. Nitrosoureas: carmustine (BCNU), lomustine (CCNU) 6. Antibody: trastazumab (Herceptin), bevacizumab (Avastin), cetuximab (Erbitux), rituximab (Rituxan) 7. Enzyme: asparaginase 8. Agents that inhibit DNA synthesis (hydroxyurea ) or damage DNA: cisplatin, carboplatin, oxaliplatin Classification of Anticancer Drugs

19. Classification of Anticancer Drugs Targeted Chemotherapy 9. Signal transduction inhibitor: imatinib (Gleevec), dasatinib, sorafinib (Nexavar), regorafenib (Stivarga), vismodegib (Erivedge) 10. Differentiation agent: all-trans retinoic acid, HDAC inhibitors (Vorinostat) 11. Hormones and hormone antagonists: prednisone, tamoxifen, aromatase inhibitors, abiraterone 12. Proteasome inhibitors: bortezomib (Velcade) 13. DNA topoisomerase I inhibitors: camptothecin, irinotecan and topotecan 14. Agents that inhibit DNA repair: PARP inhibitors 15. Arsenic trioxide: increasing the degradation of the PML-RAR  oncoprotein. 16. Inhibitors of DNA methylation: Zebularin, azacitidine and 5-aza-2 ′ deoxycytidine. 17. Chimeric toxic protein: Ontak (IL2 + Diphtheria toxin)

20. Commonly used anticancer drugs Antimetabolites- Methotrexate , 5-fluorouracil (5-FU), 6-mercaptopurine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Pemetrexed, Pentostatin, Thioguanine Alkylating Agents Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, melphalan and mechlorethamine Nitrosoureas: streptozocin, carmustine, lomustine Alkyl sulfonates: busulfan Triazines : dacarbazine (DTIC) and temozolomide Ethylenimines : thiotepa and altretamine Platinum Based: Cisplatin, oxaliplatin , and carboplatin

21. Antimetabolites: Group Characteristics Inhibit the synthesis of folic acid, purines, and pyrimidines needed to synthesize DNA Resemble NORMAL substrates (folic acid) Most inhibit DNA synthesis. Some inhibit RNA synthesis and/or function. Highly cell cycle specific, ( S or M phase) Antimetabolites are particularly effective in the treatment of leukemias Bone Marrow cell replication is profoundly inhibited. Bone marrow suppression, GI ulcerations, alopecia, and nausea and vomiting are common toxicities

22. Methotrexate (MTX) Structure Mechanism of action It is a Folic Acid Analogue Binds strongly to DHFR to reduce formation of THF, Therefore, interferes with NUCLEIC ACID synthesis.

23. Methotrixate: Clinical Uses: Broad range Well established use in (1) Acute childhood Lymphoblastic Leukemia (2) Choriocarcinoma . (3) Cancers of breast, bladder, and head & neck. (4) Useful in non-Hodgkin's lymphomas

24. Methotrixate: Adverse effects Dose limiting side effects a) Myelosuppression (Thrombocytopenia and Leukopenia, 7-10 days after Rx, Recovery 14-21 days). b) GI toxicity (Oral mucositis is early sign of GI toxicity, Severe mucositis , Small bowel ulceration & bleeding, Diarrhea requires cessation to prevent perforation of gut ) Other side effects Nephrotoxicity: I nfrequent with c onventional doses; but toxicity can be severe High doses Immunosuppression . Hepatotoxicity .

25. Flurouracil (5-FU) Structure:

26. Flurouracil (5-FU): Mechanism of action: Inhibits DNA synthesis: Inhibition of Thymidylate synthase — the most important mechanism of action (MOA) in rapidly growing tumors Activated by conversion to nucleotide 5-FU Incorporated into RNA: Interfere with RNA processing - All types, May be most important MOA in slowly growing tumors.

27. (1) Single agent: Palliative in advanced colorectal carcinoma (2) Combination: Breast cancer; Carcinomas of ovary, stomach, pancreas (3) Sequential MTX + 5-FU: Head and neck cancer Flurouracil (5-FU): Clinical Uses

28. Dose limiting: Bone marrow -- esp. with bolus administration. Leukopenia & Thrombocytopenia (9-14 days after Rx; Recovery in 5- 21). GI Toxicity -- esp. with infusion administration. usually Stomatitis & Diarrhea 4-7 days after Rx. Effect of route and schedule on adverse effects: Myelosuppression is dominant after IV bolus ; Prolonged Rx, may cause megaloblastic anemia Continuous IV Infusion: Frequently produce, stomatitis, nausea, vomiting, and diarrhea; Hepatotoxicity (elevated transaminases); myelosuppression less common Effect of peak 5-FU concentration: Acute, reversible cerebellar syndrome: somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus Flurouracil (5-FU): Adverse Drug reactions

29. Hyperpigmentation of skin is frequent and may be accompanied by photosensitivity Toxic effect of radiation to skin may be enhanced; Alopecia, acute and chronic conjunctivitis, and nail changes may be observed. Flurouracil (5-FU): Additional Adverse Drug reactions

30. Natural Products Drugs Derived from Plants Vinca Alkaloids Vincristine sulfate and Vinblastine sulfate Vinca alkaloids cause metaphase arrest and inhibit mitosis; neurotoxicity and leukopenia are the primary toxicities Taxanes : P aclitaxel and D ocetaxel Paclitaxel inhibits mitosis; peripheral neuropathy and bone marrow suppression are the most serious toxicities Epothilones: ixabepilone Estramustine

31. Vinca Alkaloids Mechanism of action Disrupt microtubule function (1) Uptake by energy dependent carrier (2) Bind to tubulin in microtubules to cause their dissolution. Contrast to Taxol which stabilizes tubules. CSS-Act at G2/M phase (3) No cross resistance between vincristine and vinblastine

32. Vinca Alkaloids: Uses (1) Drug of choice for childhood leukemias in combination with prednisone (2) Used for lymphoreticular neoplasms , carcinomas, and sarcomas

33. Vinca Alkaloids Adverse effects: (1) Severe vesicant. Must be careful of IV equipment to avoid slough. (2) Neurotoxicity: a) Mild sensory neuropathy with sensory impairment and paresthesia--Keep Rx. b) Severe paresthesias, loss of reflexes, ataxia, and muscle wasting-- stop Rx. 3) Constipation and abdominal pain - take laxatives. 4) Less hematologic effects than many other cytotoxic drugs.

34. Topoisomerase Inhibitors Interfere with enzymes (topoisomerases) which help separate the strands of DNA so they can be copied Topoisomerase I inhibitors: Topotecan and irinotecan Topoisomerase II inhibitors: Etoposide and teniposide. Not frequently used CCS- S/?G1

35. Antitumor Antibiotics Anthracycline antibiotics Daunorubicin, Doxorubicin, Epirubicin, Idarubicin Other Antitumor Antibiotics: Actinomycin -D, Mitomycin -C, and bleomycin

36. Antibiotic Drugs Inhibit the synthesis of DNA and other essential cell functions Drugs are too toxic for treatment of common bacterial infections The dose-limiting toxicity is usually bone marrow suppression and cardiac toxicity Doxorubicin is widely used to treat leukemias and a variety of solid tumors

37. Antitumor Antibiotics General characteristics Inhibit the synthesis of DNA and other essential cell functions All interact with DNA and/or RNA, but may also interact with other cellular substituents . Drugs are too toxic for treatment of common bacterial infections The dose-limiting toxicity is usually bone marrow suppression and cardiac toxicity All IV except bleomycin Tissue necrosis is only generalizable toxicity. Doxorubicin is widely used to treat leukemias and a variety of solid tumors

38. Antitumor Antibotics Mechanism of action: Generally; these drugs have duo mechanisms of action (1) DNA topoisomerase II inhibitor: Crucial to DNA replication and transcription. (2) Traditional explanations of MOA: a) intercalates between base pairs of DNA and inhibits DNA-dependent RNA synthesis. b) Generates free radicals that cause membrane damage and DNA strand breaks. May also interact with other cellular substituents LESS "phase-specific" than antimetabolites Often classified as CCNS

39. Antitumor Antibiotics: Development of Resistance (1) Alterations in Topoisomerase II activity. (2) Increased inactivation of radicals: a) Increase in glutathione-dependent enzymes, e.g., glutathione-peroxidase . b) Altered NADPH contents. (3) Increase drug efflux:

40. Antitumor Antibiotics: Clinical Indications: They have broad spectrum anti-cancer activity. Hodgkin's disease, non-Hodgkin's lymphomas, sarcomas, acute leukemia, and breast, lung, and ovarian carcinomas all responsive Activity observed in bladder tumors, and carcinomas of prostate, thyroid, endometrium , head and neck, and other solid tumors

41. Antitumor Antibiotics: Adverse effects: Three categories of toxicity: 1) Local toxicities 2) Acute toxicities 3) Chronic toxicities Local toxicities- Following Extravasation Severe local tissue necrosis to point of damaging underlying structures; If occurs, remove IV line immdeiately; Apply ice, and steroid cream Local Toxicity may also result as interaction of Doxirubicin with radiation in some tissues. Reactions include: a) Skin: ulceration and necrosis. b) Pulmonary: fibrosis and sloughing of esophageal mucosa. c) Heart, and intestinal mucosa may also be affected

42. Antitumor Antibiotics: Adverse Drug Reactions (2) Acute Toxicities a) Hematologic: Leukopenia with nadir 7-10 days; recovery typically by 21 days; Thrombocytopenia and anemia may occur but are less common b) If given too fast: "Histamine-release" syndrome; Cardiac arrest preceded by ECG changes (3) Chronic Toxicities a) Cardiomyopathy and congestive heart failure: require cessation of Rx after cumulative dose of 550 to 600 mg/m 2 ; must maintain record of total dose.

43. Alkylating Agents Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, melphalan and mechlorethamine Nitrosoureas: streptozocin, carmustine, lomustine Alkyl sulfonates: busulfan Triazines : dacarbazine (DTIC) and temozolomide Ethylenimines : thiotepa and altretamine Platinum Based: Cisplatin, oxaliplatin , and carboplatin

44. Alkylator Drugs General Characteristics Irreversibly bind to DNA and interfere with cell replication and synthesis of essential cell proteins and metabolites Some alkylators are vesicants and will cause blistering if spilled on the skin Dose-limiting toxicity is bone marrow suppression and resulting susceptibility to infection Adverse effects also include nausea, vomiting, alopecia, and ulcerations of the GI tract and mucous membranes

45. Nitrogen mustard General view: (1) Developed from mustard war gases of Word War I which were highly reactive vesicants. (2) First chemicals used for cancer Rx. (3) Not cell cycle specific, but still more active in dividing tissues. (4)"Radiomimetic" -- action on DNA resembles radiation.

46. Structural Relationship between Mustard gas and Nitrogen Mustards Mustard Gas Cl-CH2 CH2 S Cl-CH2 CH2

47. (1) Highly reactive: Form covalent bonds with DNA, RNA and protein (2) Consequences: a) DNA-DNA strand and DNA-Protein cross-links. b) Misreading of genetic code. c) DNA Chain breaks Alkylating Agents/ Nitrogen mustard: Mechanism of Action

48. (1) More toxic to bone marrow and gut than to liver and kidney, etc. (2) Infertility to both males and females. (3) Mutagenic. (4) Carcinogenic. Tumor resistance: Develops slowly & may require several genetic / biochemical changes Alkylating agents Adverse Drug Reaction

49. Alkylating Agents: Clinical Uses Wide spectrum; Lymphoreticular tissue tumors; Limited activity against sarcomas.

50. Cyclosphosphamide

51. Cyclosphosphamide Mechanism of action Hepatic cytochrome P-450 system, enzymes phosphatase and phosphamidase are primary activators (hydrolyze P-N bond) to intermediate, aldophosphamide, which nonenzymatically breaks down to -- Phosphoramide mustard (bifunctional) & Acrolein

52. Cyclosphosphamide: Pharmacokinetics Oral bioavailability = 90-100%, IV injection no local irritation Half-life -- cyclophosphamide -- 3-10 h; aldophosphamide -- 1.6 h; phosphoramide mustard -- 8.7 h. Most metabolized-- < 14% unchanged in urine.

53. Cyclosphosphamide Clinical Applications (1) Most widely used alkylating agent, in part due to availability of oral route (2) Active on lymphoproliferative diseases, e.g., Hodgkin's disease and Chronic lymphocytic leukemia (3) Significant activity vs multiple myeloma & ovarian, breast, small cell lung carcinoma (4) Many combinations.

54. Cyclosphosphamide: Adverse Drug reactions (1) Bone marrow suppression, most important leukopenia and thrombocytopenia (2) Nausea and vomiting said to be rare (3) Sterile necrotizing hemorrhagic cystitis. Acrolein is probable cause. To minimize cyctitis --high water intake and take in AM

55. Hormone Antagonists Tamoxifen, Leuprolie, Goserelin The female hormone estrogen is a growth factor for some types of breast cancer Tamoxifen is an estrogen receptor blocker that inhibits the growth of breast cancer cells Adverse effects include nausea, hot flashes, rash, and menstrual irregularities Leuprolide and goserelin inhibit the synthesis of male and female sex hormones and are used in a variety of hormonally dependent cancers

56. Other Anticancer Approaches Immunotherapy S timulate the immune systems to recognize and attack cancer cells Active immunotherapies : stimulate the body’s own immune system to fight the cancer Passive immunotherapies : do not rely on the body; instead, they use immune components (e.g. antibodies ) created outside the body. Monoclonal antibody therapy ( passive): rituximab, alemtuzumab ( Campath) Non-specific immunotherapies and adjuvants (boost the immune response ): BCG, interleukin-2 (IL-2), and interferon-alfa Immunomodulating drugs: thalidomide and lenalidomide (Revlimid ® ) Cancer vaccines (active specific immunotherapies). Provenge vaccine for advanced prostate cancer); other are being studied

57. Other agents with Anticancer A ctivity Corticosteroids: Prednisone, Methylprednisolone and dexamethasone Considered as chemotherapy if used to kill or slow the growth cancer cells Treat: lymphoma, leukemias, and multiple myeloma As anti-emetics to prevent nausea and vomiting caused by chemotherapy Used before chemotherapy to help prevent severe hypersensitivity reactions Miscelenious: L-asparaginase (enzyme), bortezomib (proteosome inhibitor)

58. General Resistance Mechanisms for Anticancer agents (1) Defective activation: Mostly for - Cyclophosphamide- requires metabolic activation - Methotrexate conversion to more active MTX-polyglutamate (2) Increased inactivation: e.g., aldehyde dehydrogenase converse cyclophosphamide to inactive metabolite. (3) Altered nucleotide pools: Can occur with antimetabolites . (4) I ncreased r epair mechanisms : for example; ability to remove cross-links affects the action of bleomycin and other DNA-directed drugs

59. (5) Altered target: Less affinity for drug, Methotrexate (Dihydrofolate reductase changes ). ( 6) Decreased target: decreased topoisomerase II, e.g., etoposide (7) Gene amplification: Methotrexate (MTX) increase dihydrofolate reductase , hence Requires more MTX to block (8) Decreased accumulation: Decreased uptake (Methotrexate -- carrier protein decreases). Increased Efflux (Multidrug Resistance, P-Glycoprotein (gP-170) in membrane, pumps drug out) General Resistance Mechanisms for Anticancer agents

60. Common Drug Toxicities for Anticancer agents Drugs affect cells with the fastest growth and reproductive rates, especially bone marrow and epithelial cells of the GI tract and skin Suppression of bone marrow and blood cell reproduction leads to anemia, infection, bleeding Gastrointestinal disturbances and ulcerations Skin ulcerations and alopecia Nausea and vomiting is common due to the high maximally tolerated doses that are required

61. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)