cancer chemotherapy-1

1. Cancer Chemotherapy-1 Dr. R. Senthil Kumar

2. Etiology: Environmental carcinogens – azo dyes, afltoxins, asbestos, benzene Viruses: herpes , papilloma , HTLV Amplification of oncogenes (proto-onco), deletion of tumor suppressor genes (p53) Shift in the control mechanisms that govern cell proliferation and differentiation Genetics vs. Environment Theory: “Genetics loads the gun; the environment pulls the triggerEtiology: Environmental carcinogens – azo dyes, afltoxins, asbestos, benzene Viruses: herpes , papilloma , HTLV Amplification of oncogenes (proto-onco), deletion of tumor suppressor genes (p53) Shift in the control mechanisms that govern cell proliferation and differentiation Genetics vs. Environment Theory: “Genetics loads the gun; the environment pulls the trigger

3. Apoptosis Programmed cell death Cascade of proteases initiate process

4. Characteristics of Cancer Cells The problem: Cancer cells divide rapidly (cell cycle is accelerated) They are “immortal” Cell-cell communication is altered uncontrolled proliferation invasiveness Ability to metastasise

5. 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

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

7. Major approaches to therapy of cancers

8. Cell Cycle = Growth, Division Normal cells… Differentiate, grow, mature, divide Regulated, balanced; cell birth=cell death Regulation: intracell signaling Hyperplasia: new cells prod’d w/ 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 Thicker cell layer better accommodates irritation Ex: bronchial epithelium chronically irritated ? ciliated columnar epithelial cells replaced by sev layers cuboidal epithelium Note: Replacement cells normal, just different Reversible 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 The growth cycle of a cell is its major determinant of responsiveness to chemotherapy. A measure of cell growth is the cell cycle. The cell cycle consists of four major phases: G1, S, G2 & M 1. G1 phase - cell prepares to make DNA. 2. S phase - DNA synthesis takes place. 3. G2 phase - synthesis of components needed for mitosis. 4. M phase - mitosis (cell division) occurs. Normal cells… Differentiate, grow, mature, divide Regulated, balanced; cell birth=cell death Regulation: intracell signaling Hyperplasia: new cells prod’d w/ 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 Thicker cell layer better accommodates irritation Ex: bronchial epithelium chronically irritated ? ciliated columnar epithelial cells replaced by sev layers cuboidal epithelium Note: Replacement cells normal, just different Reversible 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 The growth cycle of a cell is its major determinant of responsiveness to chemotherapy. A measure of cell growth is the cell cycle. The cell cycle consists of four major phases: G1, S, G2 & M 1. G1 phase - cell prepares to make DNA. 2. S phase - DNA synthesis takes place. 3. G2 phase - synthesis of components needed for mitosis. 4. M phase - mitosis (cell division) occurs.

9. Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high 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 Effective in low growth fraction as well as high growth fraction solid tumors Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high 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 Effective in low growth fraction as well as high growth fraction solid tumors

10. Cancer Chemotherapy 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. 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.

11. Cell cycle specific drugs (CCS) or phase specific: Antimetabolites: Methotrexate, 6-Mercaptopurine Antibiotic: Bleomycin Taxane: Paclitaxel Epipodophyllotoxins: Etoposide, Teniposide Vinca alkaloids: Vinblastine, Vincristine Act mainly on dividing cells Most effective in hematologic and solid tumors with high growth fraction Cell cycle non-specific (CCNS) or phase non specific drugs: Alkylating agents: Cyclophosphamide, Busulfan, Mechlorethamine, Melphalan. Anticancer antibiotics: Doxorubicin, Daunorubicin, Mitomycin, Actinomycin D. Camptothecins: Topotecan, Irinotecan Metal complexes: Cisplatin, Carboplatin CCNS drugs act on dividing as well as resting cells Effective in low growth fraction as well as high growth fraction solid tumors Cell cycle specific drugs (CCS) or phase specific: Antimetabolites: Methotrexate, 6-Mercaptopurine Antibiotic: Bleomycin Taxane: Paclitaxel Epipodophyllotoxins: Etoposide, Teniposide Vinca alkaloids: Vinblastine, Vincristine Act mainly on dividing cells Most effective in hematologic and solid tumors with high growth fraction Cell cycle non-specific (CCNS) or phase non specific drugs: Alkylating agents: Cyclophosphamide, Busulfan, Mechlorethamine, Melphalan. Anticancer antibiotics: Doxorubicin, Daunorubicin, Mitomycin, Actinomycin D. Camptothecins: Topotecan, Irinotecan Metal complexes: Cisplatin, Carboplatin CCNS drugs act on dividing as well as resting cells Effective in low growth fraction as well as high growth fraction solid tumors

12. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS) Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high 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 Effective in low growth fraction as well as high growth fraction solid tumors Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high 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 Effective in low growth fraction as well as high growth fraction solid tumors

13. Log kill hypothesis According to the log-kill hypothesis, chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose 1. Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery 2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy

14. Log kill hypothesis:

15. LOG kill hypothesis The example shows the effects of tumor burden, scheduling, initiation/duration of treatment on patient survival. The tumor burden in an untreated patient would progress along the path described by the RED LINE – The tumor is detected (using conventional techniques) when the tumor burden reaches 109 cells The patient is symptomatic at 1010-1011 cells Dies at 1012 cells. DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate) GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used. DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate) GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.

16. Cancer Chemotherapy Combinations of agents with differing toxicities & mechanisms of action are often employed to overcome the limited cell kill of individual anti cancer agents. Each drug selected should be effective alone 3 advantages of combination therapy: 1. Suppression of drug resistance - less chance of a cell developing resistance to 2 drugs than to 1 drug. 2. Increased cancer cell kill - administration of drugs with different mechanisms of action. 3. Reduced injury to normal cells - by using a combination of drugs that do not have overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone.

18. Modes of Resistance to Anticancer Drugs

19. General problems with anticancer drugs Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis. They also affect rapidly dividing normal cells. This leads to toxicity which are usually severe. To greater or lesser extent the following toxicities are exhibits by all anticancer drugs.

20. ADR of Antineoplastic Drugs in Humans

21. Distinctive Toxicities of Some Anticancer Drugs

22. Proliferating cells are especially sensitive to chemotherapy because cytotoxic drugs usually act by disrupting DNA synthesis or mitosis, cellular activities that only proliferating cells carry out. Unfortunately, toxicity to the anticancer agents is to any rapidly dividing cells. (e.g. bone marrow, hair follicles, sperm forming cells).

23. Prevention or Management of Drug Induced toxicities The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications E.g. mesna is given to prevent hemorrhagic cystitis by cyclophosphamide Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy

24. Anti-cancer drugs