Section I Basic Pharmacology of Anticancer Drug 1. Classification

Plant-derived products Hormonal agent (1) According to chemical constitution and resource Alkylating agent Antimetabolites Antibiotics Plant-derived products Hormonal agent

Alkylating agent Melphalan Chlorambucil Cyclophosphamide Mechlorethamine Melphalan Chlorambucil

Antimetabolites Folic acid analogue: methotrexate Pyrimidines:fluorouracil, cytarabine Purines: thioguanine, mercaptopurine

Antibiotics Anthracyclines Dactinomycin Bleomycin Mitomycin

Plant-derived products Vinca alkaloids Etoposides Taxanes

Hormonal agent Hormone antagonists Hormone agonists

Agents affecting biosynthesis of nucleic acid （2）According to biochemistry mechanisms of antitumor effect Agents affecting biosynthesis of nucleic acid Agents affecting structure and function of DNA Agents affecting transcription process and interrupting synthesis of RNA Agents interfering with the formation and function of proteins. Agents affecting hormone homeostasis

2. Mechanism of pharmacologic action （1） Cell biology mechanisms of antitumor effect （2） Biochemistry mechanisms of antitumor effect

（1） Cell biology mechanism of antitumor effect Cell Cycle-Nonspecific (CCNS) Agents: Alkylating agent, Antibiotics, Platinum antitumor compound Cell Cycle-Specific (CCS) Agents: Methotrexate: S phase Vinca alkaloid: M phase Both normal cells and tumor cells go through a growth cycle (Figure 38.4). However, normal and neoplastic tissue may differ in the number of cells that are in the various stages of the cycle. Chemotherapeutic agents that are effective only in replicating cells, that is those cell- "at are cycling, are said to be cell-cycle specific (see Figure, +), whereas other agents are cell-cycle nonspecific. The nonspe- cific drugs such as the alkylating agents, although generally more toxic in cycling cells, are also useful against tumors with a low percentage of replicating cells.

（2）Biochemistry mechanisms of antitumor effect Affecting biosynthesis of nucleic acid Dihydrofolate Reductase Inhibitor：Methotrexate synthesis of tetrahydrofolate synthesis of thymidylate, purine nucleotides formation of DNA, RNA

b) Pyrimidine Antagonists：Fluorouracil deoxythymidylate synthetase deoxyuridylic acid deoxythymidylic acid DNA synthesis

C) Purine Antagonists ： Mercaptopurine HGPRT 6-thioinosinic acid purine nucleotide interconversion

d) Ribonucleotide Reductase Inhibitor: Hydroxyurea cytidylic acid deoxycytidylic acid DNA synthesis

5'-mononucleotide (AraCMP) triphosphate (AraCTP) e) DNA Polymerase Inhibitor： Cytarabine (ara-C ) 5'-mononucleotide (AraCMP) triphosphate (AraCTP) DNA polymerase DNA synthesis

Affecting structure and function of DNA DNA Cross-linkage agent: alkylating agents Platinum antitumor compound: Cisplatin Antibiotics: Bleomycin Topoismerase inhibitor: camptothecins Bifunctional alkylating agents,such as the nitrogen mustards, may form covalent bonds with each of two adjacent guanine residues. Such interstrand cross-linkages will inhibit DNA replication and transcription. Intrastrand cross-links also may be produced between DNA and a nearby protein.

Affecting transcription process and interrupting synthesis of RNA Anthracyclin Dactinomycin

d. Interfering with the formation and function of proteins Microtubule inhibitors: Vinca alkaloid tubulin polymerization extension of microtubules termination of mitotic division

b) Agent influence amino acid supply Asparaginase L-asparagine aspartic acid protein synthesis

Affecting hormone homeostasis Estrogens and antiestrogen Androgens and antiandrogen Progestogens glucocorticoid

SectionII Problems associated with chemotherapy 1. Resistance Inherently resistant Acquired resistance Multidrug Resistance Many patients undergoing chemotherapy fail to respond to treatment from the outset; their cancers are resistant to the available agents. Some neoplastic cells, for example, melanoma, are inherently resistant to most anticancer drugs. Other tumor types may be selected for or acquire resistance to the cytotoxic effects of the medication, particularly after prolonged administration of low drug doses. The development of drug resistance is minimized by short-term, intensive, intermittent therapy with combinations of drugs. Drug combinations are also effective against a broader range of resistant cell lines in the tumor population. A variety of mechanisms are responsible for drug resistance; each is considered separately under the particular drug. Tumor cells may become generally resistant to a variety of cytotoxic drugs on the basis of decreased uptake or retention of the drugs. This form of resistance is termed multidrug, resistance, Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for "permeabil- ity" glycoprotein, is responsible for multidrug resistance (MDR). The resistance is due to ATP-dependent pumping of the drug out of the cell, associated with the presence of P-glyco-protein. Cross-resistance among structurally unrelated agents occurs.

Multidrug Resistance Tumor cells may become generally resistant to a variety of cytotoxic drugs on the basis of decreased uptake or retention of the drugs P-glycoprotein

2. Toxicity (1) short term toxicity Common adverse effects: Bone Marrow Toxicity: hormone, Bleomycin, asparaginase (b) Gastrointestinal Tract Toxicity (c) Hair Follicle Toxicity Chemotherapy may result in the destruction of actively proliferating hematopoietic precursor cells. White blood cell and platelet counts may in turn be decreased, resulting in an increased incidence of life-threatening infections and hemorrhage.Maximum toxicity usually is observed 10 to 14 days after initiation of drug treatment, with recovery by 21 to 28 days. The nausea and vomiting frequently observed after anticancer drug administration are actually thought to be caused by a stimulation of the vomiting center or chemoreceptor trigger zone in the central nervous system (CNS) rather than by a direct gastrointestinal effect. Most anticancer drugs damage hair follicles and produce partial or complete alopecia. Hair usually regrows normally after completion of chemotherapy. The duration of the side effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities are irreversible.

Uncommon adverse effects: (a) Pulmonary toxicity: Bleomycin (b) Hepatotoxicity： L-Asparaginase 、Cyclophosphamide (c) Renal toxicity：Cyclophosphamide (d) Neurotoxicity：Vincristine、Cisplatin (e) Allergic response：L-Asparaginase、Bleomycin、Paclitaxel

(2) Long term toxicity Treatment-induced tumors Infertility and deformability Since most antineoplastic agents are mutagens, neoplasms (for example, acute nonlymphocytic leukemia) may arise 10 or more years after the original cancer was cured. Treatment-induced neoplasms are especially a prob- lem after therapy with alkylating agents

Thank you！

Test What is mechanism of antimicrobial action and corresponding antimicrobial agents? What is the mechanism of bacterial resistance to an antimicrobial agent? Which drug is first chosen to treat penicillin allergic shock, and why? What are features in three generations of cephalosporins? What are antibacterial spectrum and clinical uses of erythromycin?

What is antibacterial action of quinolones? What is composition of co-trimoxazole and adventage of co-trimoxazol? Which species are anticancer agents divided into, according to biochemistry mechanisms of antitumor effect? Which antibacterial agents are contraindicated in treatment of newborn infection and why? Which drug is used for treatment of infection caused by staphylococcus aureus?