3. Treatment Goal: • The ultimate goal is a cure: • long-term, disease-free survival • If not attainable control of the disease (stop the cancer from enlarging and spreading) • to extend survival • maintain the best quality of life.

4. In either case, the neoplastic cell burden is initially reduced by: • Surgery and/or by radiation • followed by chemotherapy, hormonal therapy, immunotherapy, or a combination of these treatment modalities.

5. Treatment Indications for treatment: • When neoplasms are disseminated and are not amenable to surgery. • Adjuvant chemotherapy: following surgery and radiation treatment to attack micrometastases. • Neoadjuvant chemotherapy: prior to the surgical procedure in an attempt to shrink the cancer. • Maintenance chemotherapy: given in lower doses to assist in prolonging a remission.

7. Challenges of Chemotherapy A. Failure of early detection B. 100% kill required – multiple rounds of treatment, multiple agents

8. Challenges of Chemotherapy C. Drug resistance • Increased DNA repair • Formation of trapping agents: eg, glutathione, which interact with anticancer drugs that form reactive electrophilic species. • Changes in target enzymes 4. Decreased activation of prodrugs: a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. 5. Inactivation of anticancer drugs 6. Decreased drug accumulation

9. Challenges of Chemotherapy D. Narrow therapeutic index/toxic side effects 1. Bone marrow suppression 2. Mucositis throughout GI tract 3. Increased risk of infection, febrile neutropenia , 4. Alopecia 5. Nausea, vomiting and cachexia 6. Damage to reproductive system 7. Neurotoxicity 8. DNA damage – treatment can be mutagenic, carcinogenic and teratogenic

12. Anti-cancer drugs • The three mechanism of actions of anticancer agents : • Damage the DNA of the affected cancer cells. • Inhibitthe synthesis of new DNA strands and integrity. • Inhibit mitosisor the actual splitting of the original cell into two new cells.

15. All cells undergo cycling which can be subdivided in a phase named G0(the resting phase) 4 cycling phase named,G1, S, G2 and M. Cell cycle kinetics :

19. Legend Drug Class Sub-class Prototype Drug Trimetrexate Pemetrexed Cytarabine Gemcitabine Capecitabine Thioguanine Fludarabine Phosphate Cladribine

20. Antimetabolites Ø Mechanism of Action: Ø structural analogs of normal molecules required for the synthesis of DNA, RNA, amino acids and vitamins Ø interfere with nucleotide and nucleic acid synthesis, or incorporation into DNA S phase specific Ø Ø Most effective for rapidly proliferating tumors, esp. leukemias , lymphomas Ø All cause myelosuppression

24. 2. Fludarabine Phosphate • Chronic lymphocytic leukemia • Adenosine analog • Inhibits ribonucleotide reductase and DNA polymerase

25. 3. Cladribine (2-CdA) • Hairy cell leukemia (80% response) non-Hodgkin’s lymphoma • Adenosine analogue: Deoxyadenosine resistant to adenosine deaminase. • Causes DNA strand breaks and loss of NAD • Cladribine causes decreased CD4 and CD8 counts; how-ever, this effect is transient. • administered intravenously.

28. X MTX 5 - FU X Figure 2. This figure illustrates the effects of MTX and 5 - FU on the biochemical pathway for reduced folates.

30. Cytarabine (ara-C) • Acute myelogenous leukemia • Cytosine analog • Inhibits DNA polymerase • Cytarabine is highly myelosuppressive and can produce severe leukopenia, thrombocytopenia, and anemia. • gastrointestinal disturbances.

31. 3. Gemcitabine • inhibits DNA synthesis via chain termination. • It is an intravenous agent used for: • pancreatic cancer • non-small cell lung cancer • bladder cancer. • Myelosuppression is the main limiting effect.

32. 4. Capecitabine • is a fluoropyrimidine carbamate prodrug that is converted to 5-FU once ingested. • It is an oral agent used for metastatic breast cancer when patients are resistant to paclitaxel/anthracycline therapy and for metastatic colorectal cancer. • Dermatitis and myelosuppression • may elevate bilirubin levels

36. Taxanes (pacific yew) • Paclitaxel & Docetaxel • Cisplatin-resistant solid tumors • Block tubulin depolymerization and inhibit mitosis, CSS = M-phase • Peripheral neuropathy • Resistance due to MDR-1 gene; drug pumped out of cell

46. Alkylating agents cause fragmentation Alkylating agents cause cross linking Alkylating agents cause mis-pairing

49. Melphalan • Especially useful for multiple myeloma • Well absorbed orally, no alopecia, no local irritation • Toxicity: • Myelosuppression • Nausea and vomiting infrequent