Antineoplastic agents

Anticancer agents

1. ANTINEOPLASTIC AGENTS

2. Introduction #1 Normal cells… Differentiate, grow, mature, divide Regulated, balanced; cell birth=cell death Regulation: intracell signaling Hyperplasia: new cells production with growth stimulus via hormones, endogenous signals Ex: hyperplasia of endometrial tissue during menstrual cycle is normal and necessary BUT if intense, prolonged demand May  cell structural, functional abnormalities Metaplasia : replacement of one cell type by another

3. Introduction #2 Dysplasia : replacement cells disordered in size, shape Incr’d mitosis rate Somewhat reversible, often precancerous Neoplasia : abnormal growth/invasion of cells “New growth” Neoplasm = tumor Irreversible Cells replicate, grow w/out control

4. Neoplasms Tumors = groups of neoplastic cells Two major types: benign, malignant Benign – “noncancerous” Local; cells cohesive, well-defined borders Push adjacent tissue away Doesn’t spread beyond original site Often has capsule of fibrous connective tissue Malignant – grow more rapidly; often called “cancer” Not cohesive; seldom have capsule Irregular shape; disrupted architecture Invade surrounding cells Can break away to form second tumor “Metastasis” from 1 o to 2 o site

5. Cancer ( Neoplastic ) Cancer occurs after normal cells have been transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes. Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties. These changes lead to uncontrolled cell division and many result in the invasion of previously unaffected organs, a process called metastasis

6. Oncogenesis = Process of Tumor Development Probably multi-step process Initation = important change introduced into cell Probably through DNA alteration >1 event probably needed for tumor production Reversible unless and until: Promotion = biochem event encourages tumor form’n Gen’ly need both initiation and promotion Initiators, promoters may be toxins OR radiation OR viruses)

7. The Goal of Cancer Treatments Curative Total irradication of cancer cells Curable cancers include testicular tumors, Wills tumor Palliative Alleviation of symptoms Avoidance of life-threatening toxicity Increased survival and improved quality of life Adjuvant therapy Attempt to eradicate microscopic cancer after surgery e.g. breast cancer & colorectal cancer

8. Six Established Rx Modalities Surgery Radiotherapy Chemotherapy Endocrine therapy Immunotherapy Biological therapy

9. The Basic Concept of Cell Generation Cycle Cell Cycle = Growth, Division

10. Cell Cycle Phases Synth DNA precursors, proteins, etc. Premitotic synth of structures, mol’s

11. Cycle Checkpoints

12. After completion of mitosis, the resulting daughter cells have two options: (1) they can either enter G1 & repeat the cycle or (2) they can go into G0 and not participate in the cell cycle. (Quiescent phase outside cell cycle) Growth fraction - at any particular time some cells are going through the cell cycle whereas other cells are resting. The ratio of proliferating cells to cells in G0, is called the growth fraction. A tissue with a large percentage of proliferating cells & few cells in G0 has a high growth fraction. Conversely, a tissue composed of mostly of cells in G0 has a low growth fraction

13. Apoptosis Review In healthy cells, survival factors signal activation anti-apoptotic mechanisms Cytokines, hormones, cell contact factors Programmed cell death Cascade of proteases initiate process Second pathway activated d by intracell signals, e.g. DNA damage Players are p53 gene & prot ; mitochondrial cytochrome c; Apaf-1 ( prot ); caspase 9

14. Uncontrolled Proliferation Result of activation proto- oncogenes or inactivation of tumor suppressor genes Change in growth factors, receptors Incr’d growth factors prod’d Change in growth factor pathways 2 nd messenger cascades ( esp tyr -kinase receptor cascades) Change in cell cycle transducers Cyclins , Cdk’s , Cdk inhibitors Change in apoptotic mech’s Change in telomerase expression Change in local blood vessels  angiogenesis

15. Anticancer Drugs Alkylating Agent Antimetabolite Antibiotics Alkaloid Hormones Others （ cis -platinum ， carboplatin ， lobaplatin etc ）

16. General problems with anticancer drugs Side effects greatest in other rapidly-dividing cells Bone marrow toxicity Impaired wound healing Hair follicle damage Gi epith damage Growth in children Gametes Fetus May themselves be carcinogenic

17. Alkylating Agents One of the frightening developments of World War I was the introduction of chemical warfare. These compounds were known as the nitrogen mustard gases. The nitrogen mustards were observed to inhibit cell growth, especially of bone marrow. Shortly after the war, these compounds were investigated and shown to inhibit the growth of cancer cells.

18. Alkylating Agents 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.

19. Classification of Alkylating Agents Bis Chloroethyl Amines ： Cyclophosphamide , Chlormethine , Chlorambucil , Sarcolysine Nithrosoureas ： Carmustine ， Lomustine Ethyeneammonium or Aziridines ： Thiotepa ， triethylene melamine Alkysulfonates ： Busulfan

20. Resistance of Alkylating Agents Resistance to alkylating agents has several causes: Membrane transport may be decreased. The drug may be bound by glutathione (GSH) via GSH-S- transferase or metallothioneins in the cytoplasm and inactivated. The drug may be metabolized to inactive species.

21. Adverse Effects of Alkylating Agents Myelosuppression is the dose-limiting adverse effect for alkylating agents. Nausea and vomiting are common as are teratogenesis and gonadal atrophy, although in the latter cases these are variable, according to the drug, its schedule, and route of administration. Treatment also carries a major risk of leukemogenesis and carcinogenesis.

22. Alkylating Agents—— Cyclophosphamide It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard The active drug alkylates nucleophilic groups on DNA bases Particularly at the N-7 position of guanine This leads to cross linking of bases, abnormal base pairing and DNA strand breakage Indications ： It is used in the treatment of chronic lymphocyctic leukemia, non-Hodgkin’s lymphomas, breast and ovarian cancer, and a variety of other cancers. It is also a potent immunosuppressant, it is used in the management of rheumatoid disorders and autoimmune nephritis. Adverse Effects: Alopecia, nausea, vomiting, myelosuppression , and hemorrhagic cystitis.

23. Alkylating Agents—— Nitrosoureas Carmustine , Lomustine , Semustine Pharmacokinetics: Nitrosoureas are highly lipophilic and reach cerebrospinal fluid concentrations that are about 30% of plasma concentrations. Indications: Because of their excellent CNS penetration, carmustine and lomustine have been used to treat brain tumors.

24. Alkylating Agents—— Phenylalanine Nitrogen Mustard Melphalan is a nitrogen mustard that is primarily used to treat multiple myeloma (plasma cell myeloma), breast cancer, and ovarian cancer.

25. lkylating Agents—— Alkysulfonates Busulfan Indications: Busulfan is administered orally to treat chroic granulocytic leukemia and other myeloproliferative disorders. Adverse Effects: Busulfan produces advers effects related to myelosuppression . It only occasionally produces nausea and vomitting . In high doses, it produces a rare but sometimes fatal pulmonary fibrosis, ” busulfan lung”.

26. Alkylating Agents—— Thiotepa Thiotepa is converted rapidly by liver mixed-function oxidases to its active metabolite triethylenephosphoramide (TEPA); it is active in bladder cancer

27. Antimetabolites 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 .

28. Classification of Antimetabolites Folic acid Antagonists: MTX Purine Antagonists: 6MP 6TG Pyrimidine Antagonists ： 5FU araC HU

29. Antimetabolites —— Folic Acid Antagonist Methotrexate （ MTX ） Mechanism of Action ： 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.

30. Antimetabolites —— Folic Acid Antagonist Methotrexate （ MTX ） Indications ： The use of MTX in the treatment of choriocarinoma , a trophoblastic tumor, was the first demonstration of curative chemotherapy. It is especially effective for treating acute lymphocytic leukemia and for treating the meningeal metastases of a wide range of tumors. Adverse Effects ： MTX is myelosuppressive , producing severe leukopenia , bone marrow aplasia , and thrombocytopenia. This agent may produce severe gastrointestinal disturbances. Renal toxicity may occur because of precipitation ( crystalluria ) of the 7-OH metabolite of MTX.

31. Antimetabolites —— Purine Antagonists 6-Mercapapurine （ 6-MP ） The drugs are believed to act similarly to inhibit purine base synthesis, although their exact mechanisms of action are still uncertain. Indications: Mercaptopurine is used primarily for the maintenance of remission in patients with acute lymphocytic leukemia and is given in combination with MTX for this purpose. Adverse Effects: Well tolerate. Myelosuppression is generally mild with thioguanine.Long -term mercaptopurine use may cause hepatotoxicity .

32. Antimetabolites —— Pyrimidine Antagonists 5-Fluorouracil (5-FU) Mechanism of Action ： Fluorouracil is an analogue of thymine in which the methyl group is replaced by a fluorine atom. It has two active metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits thymidylate synthetases and prevents the synthesis of thymidine , a major building block of DNA. 5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function.

33. Antimetabolites —— Pyrimidine Antagonists 5-Fluorouracil (5-FU) Indications ： Fluorouracil is exclusively used to treat solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck. Adverse Effects ： Fluorouracil may cause nausea and vomiting, myelosuppression , and oral and gastrointestinal ulceration. Nausea and vomitting are usually mild. With fluorouracil, myelosuppression is more problematic after bolus injections, whereas mucosal damage is dose-limiting with continuous infusions.

34. Antimetabolites —— Pyrimidine Antagonists Cytarabine Indications ： Cytarabine has a narrow clinical spectrum and is primarily used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia. Adverse Effects : High doses of cytarabine can damage the liver, heart, and other organs.

35. Anthracyclines : Doxorubicin ( Adriamycin ) Daunorubicin Bleomysin Dactinomycin Mitomycin Antibiotics

36. Doxorubicin & Daunorubicin These drugs intercalate between base pairs, inhibit topoisomerase II and also generate free radicals They block RNA and DNA synthesis and cause strand scission

37. ADR Cardiac toxicity (due to generation of free radicals) Acute form: arrthythmias , ECG changes, pericarditis , myocarditis Chronic form: *** Dilated cardiomyopathy , heart failure ****Rx with dexrazoxane This is an inhibitor of iron mediated free radical generation Bone marrow depression, Total alopecia Radiation recall reaction

38. Mitomycin C: Mechanism: Mitomycin C is an antineoplastic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis. Indications: It is primarily used in combination with vinvristine as salvage therapy for breast cancer. Adverse Effects: Mitomycin produces delays and prolonged myelosuppression that preferentially affects platelets and leukocytes

39. Actinomycin D: Actinomycin D intercalates DNA and thereby prevents DNA transcription and messenger RNA synthesis. The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and the treatment of pediatric tumors, such as Wilms ’ tumor and Ewing’s sarcoma.

40. Bleomycin : Mechanism: The drug has its greatest effect on neoplastic cell in the G2 phase of the cell replication cycle.Although bleomycin intercalates DNA, the major cytotoxicity is believed to result from ironcatalyzed free radical formation and DNA strand breakage. Indications: It is useful in Hodgkin’s and non-Hodgkin’s lymphomas, testicular cancer, and several other solid tumors. Adverse Effects: Bleomycin produces very little myelosuppression . The most serious toxicities of Bleomycin are pulmonary and mucocutaneous reactions.

41. Anti-Cancer Plant Allaloids Tubulin -Binding Agents Vinca Alkaloids: The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly, causing cells to arrest in the late G2 phase by preventing formation of mitotic filaments for nuclear and cell division Vinblastine,vincristin , vindesine and vinorelbine are all alkaloids derived from the periwinkle plant ( Vinca rosea ).

42. Anti-Cancer Plant Allaloids Vinca Alkaloids Indications: Vinblastine is used in combination with Bleomycin and Cisplatin for metastatic testicular tumors. Vincristine is used in combination with prednisone to induce remission in childhood leukemia. Vinorelbine is used to treat non-small-cell lung cancer and breast cancer. ADR Severe neurotoxicity Paresthesias Loss of reflexes Foot drop Ataxia

43. Anti-Cancer Plant Allaloids Paclitaxel & Docetaxel ( Taxans ) These drugs act by interfering with mitotic spindle They prevent micotubule disassembly into tubulin monomers Therapeutic Uses. Docetaxel and paclitaxel have become central components of regimens for treating metastatic ovarian, breast, lung, and head and neck cancers ADR Neutropenia Peripheral neuropathy

44. Platinum Compound Cisplatin : Mechanism of Action: Cisplatin binds to guanine in DNA and RNA, and the interaction is stabilized by hydrogen bonding. The molecular mechanism of action is unwinding and shortening of the DNA helix. Cisplatin : Indications: Cisplatin has efficacy against a wide range of neoplasms . It is given intravenously as a first-line drug for testicular, ovarian, and bladder cancer, and it is also useful in the treatment of melanoma and a number of other soild tumors. Adverse Effect: Cisplatin produces relatively little myelosuppression but can cause severe nausea, vomiting, and nephrotoxicity .

45. Carboplatin : Indication: Carboplatin has a similar spectrum of activity, but it is approved only as a second-line drug for ovarian cancer.

46. Hormones Several types of hormone-dependent cancer (especially breast, prostate, and endometrial cancer) respond to treatment with their corresponding hormone antagonists. Estrogen antagonists are primarily used in the treatment of breast cancer, whereas androgen antagonists are used in the treatment of prostate cancer. Corticosteroids are particularly useful in treating lymphocytic leukemias and lymphomas.

47. Hormones Estrogens: Estrogens inhibit the effects of endogenous androgens and androgen-dependent metastatic prostatic carcinoma. Diethylstilbestrol is usually the agent of choice. Cardiac and cerebrovascular complications and carcinoma of the male breast are potential adverse effects.

48. Hormones Androgens: Androgen activity in breast cancer is similar to that of estrogens, perhaps for the same mechanistic reasons. Virilizing effects and hepatic toxicity make them unacceptable to most patients. Fluoxymesterone is the most widely used agent. Danazol has use in hematology in aplastic anemia and congenital anemias .

49. Hormones GnRH analogs Leuprolide , gosarelin and naferelin Effective in management of Prostatic carcinomas When given in constant doses they inhibit release of pituitary LH and FSH These drugs suppress gonadal function due to down regulation and desensitization of Gn -RH receptors ADR Leuprolide may cause gynecomastia , hematuria , impotence and testicular atrophy

50. Hormones Glucocorticoids : They are integral components of curative therapy for acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease. Glucocorticoids have essential roles in the prevention of allergic reaction, emesis control, relief of intracranial hypertension or spinal cord compression in neurologic complications, and pain relief.

51. Sex hormone antagonists Tamoxifen It is a SERM Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat tissue It is used in receptor positive breast carcinoma Also useful in progestin resistant endometrial carcinoma ADR: Hot flushes, vaginal bleeding and venous thrombosis Other drugs Flutamide : androgen receptor antagonist used in prostatic carconima ADR for flutamide includes: gynecomastia , hot flushes

52. Aromatase inhibitors The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione This takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. Aromatase inhibitors decrease the production of estrogen in these women. Anastrozole and Letrozole These drugs inhibit the aromatase enzyme **** Used in Tx of postmenopausal women with metastatic breast ca (1 st line drug) ADR includes: bone pain and peripheral edema

53. Miscellaneous agents Asparaginase , imatinib , interferons , monoclonal antibodies Asparaginase L- Asparaginase catalyzes the deamination of asparagine to aspartic acid and ammonia. L- Asparaginase is used in combination therapy to treat childhood acute lymphocytic leukemia Its mechanism of action is based on the fact that some neoplastic cells require an external source of asparagine because of their limited capacity to synthesize sufficient amounts of that amino acid to support growth and function. L- Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesis ADR Acute pancreatitis

54. Imatinib Example of a drug, whose development was guided by knowledge of a specific oncogene Used for the treatment of chronic myeloid leukemia Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl oncogene

55. Interferons Human interferons have been classified into three types—α, β, and  —on the basis of their antigenicity . The α interferons are primarily leukocytic , whereas the β and  interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively. Recombinant DNA techniques in bacteria have made it possible to produce two species designated interferon-α-2a and -2b used in Tx of neoplastic diseases. ***Interferon-α-2a is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma. ***Interferon-α-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma.

56. Monoclonal Antibodies They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type. Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse ( murine ) antibodies. Currently, several monoclonal antibodies are available for the treatment of cancer. Trastuzumab , rituximab , bevacizumab , and cetuximab

57. Prevention/management of Cancer Chemotherapy induced ADR Nausea and vomiting : 5-Ht3 antagonist ( ondansetron ) Bone marrow suppression : Filgrastim , Sargromastim (colony stimulating factors) MTX toxicity : Leucovorin Cyclophosphamide toxicity : MESNA Cisplatin toxicity : Amifostine Anthracycline toxicity ; Dexaroxazone