1. Section I Basic Pharmacology of Anticancer Drug
1. Classification

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

3. Alkylating agent Melphalan Chlorambucil
Cyclophosphamide Mechlorethamine
Melphalan
Chlorambucil

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

5. Antibiotics
Anthracyclines
Dactinomycin
Bleomycin
Mitomycin

6. Plant-derived products
Vinca alkaloids
Etoposides
Taxanes

7. Hormonal agent
Hormone antagonists
Hormone agonists

8. 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

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

10. （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.

11. （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

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

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

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

15. 5'-mononucleotide (AraCMP) triphosphate (AraCTP)
e) DNA Polymerase Inhibitor：
Cytarabine (ara-C )
5'-mononucleotide (AraCMP)
triphosphate (AraCTP)
DNA polymerase
DNA synthesis

16. 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.

17. Affecting transcription process and interrupting synthesis of RNA
Anthracyclin
Dactinomycin

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

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

20. Affecting hormone homeostasis
Estrogens and antiestrogen
Androgens and antiandrogen
Progestogens
glucocorticoid

21. 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.

22. 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

23. 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.

24. 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

25. (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

26. Thank you！

27. 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?

28. 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?