1. Cancer therapeutic drugs

2. Introduction of cancer therapy
At present, about 50% of patients with cancer can be cured, with chemotherapy contributing to cure in 10–15% of patients.
Chemotherapy provides palliative rather than curative therapy at present. Effective palliation results in temporary improvement of the symptoms and signs of cancer and enhancement in the overall quality of life.
Ideal anticancer drugs would eradicate cancer cells without harming normal tissues. Unfortunately, no currently available agents meet this criterion, and clinical use of these drugs involves a weighing of benefits against toxicity in a search for a favorable therapeutic index.

3. Problem exiting in anticancer drug
1.Low efficacy to most of cancer
2.Severe toxicity
(1)Bone marrow suppresion
(2)GI
(3) alopecia
(4)Hepatic and renal toxicity
3.Resistance
(1) Absence the response to first exposure, e.g. MM
(2) Acquired resistance

4. Classification 1. According to the chemical structure and source
(1) Alkylating agents (Busulfan, Cyclophosphamide)
(2) Anti-metabolites (folic acid, pyrimidine, purine analogue)
(3) Antineoplastic antibiotics (bleomycin, actinomycin)
(4) Antineoplastic nature products (taxol, vinblastin)
(5) Hormone (GC, estrogen, androgen)
(6) Others (cisplatin, carboplatin)

5. Classification 2. According to the antineoplastic mechanism
(1) Disturbe the nucleic acid synthesis (Ara-C, 5-FU)
(2) Disrupt the DNA stucture and function (CTX, busulfan)
(3) Distrube the transcription and RNA synthesis (actinomycin D, daunorubcin)
(4) Disturbe the protein synthesis (taxol, vinblastin)
(5) Affecting the balance of hormone (GC, estrogen, androgen)

6. Classification 3. According to cell cycle specificity CCNSA
Alkylating agents:
Antineoplastic antibiotics:
(2) CCSA: vinblastin M stage
anti-metabolites S stage

8. Kinetics of cell proliferation
Two cell types
1.Proliferating cells: log formulation
　　　　　　　 Proliferating cell number
Growth fraction =
( GF) 　 total cell number
GF high：early. Acute leukemia, Hodgkin's disease, and
choriocarcinoma，sensitive to antineoplastic agents
GF low：late. Chronic leukamia，solid tumor, low sensitivity↓

9. 2.Non-proliferating cells
not sensitive to drug (G0 phase), recurrence

10. Resistance 1. Nature resistance 2. Acquired resistance
MDR (multidrug resistance)
PDR (pleiotropic drug resistance)
mutation
the larger cancer the more possibility of resistance (times of division)

11. Antineoplastic agents
1. Disturbe the nucleic acid synthesis
MTX, 6-MP, 5-FU, Arac, HU
structure analogues of folic acid, purine, pyramidine, neucleic acid
(1)compititively binding to the enzymes
(2) structure analogues of metabolites
results in：inhibition of DNA, RNA and protein synthesis

12. Common properties CCSA: S
1.Slow
2.Most of them are effective on leukemia (except for 5-FU)
3.Resistance after long-term exposure
4.Low selection, and common side effects

13. 5-fluorouracil; 5-FU Pharmacological action：
5-Fluorouracil (5-FU) is a prodrug and undergoes a complex series of biotransformation reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme thymidylate synthase and the reduced folate N5,10-methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate. This results in inhibition of DNA synthesis through "thymineless death."
5-FU is converted to 5-fluorouridine-5'-triphosphate (FUTP), which is then
incorporated into RNA, where it interferes with RNA processing and mRNA translation.
In addition, 5-FU is converted to 5-fluorodeoxyuridine-5'-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function.
Thus, the cytotoxicity of fluorouracil is felt to be the result of effects on both DNA- and RNA-mediated events.

14. 5-fluorouracil; 5-FU Indication：widely used Toxicity:
choriocarcinoma ：first choice, ACTD
colorectal cancer, liver cancer (25%)
head and neck (30%), ovary cancer,bladder cancer, thyroid cancer
Toxicity:
Myelosuppression GI
bleeding diarrhea

15. Methotrexate；MTX
mechanism：
structure analogue of folic acid, dihydrofolate reductase inhibitor
1. FH FH dTMP ↓ DNA ↓
2. purine nucleotides↓ RNA, protein ↓
Indication：Leukemia, choriocarcinoma
Side-effects：
Mucositis,
Diarrhea
Bone marrow depression with leukopenia and thrombocytopenia

16. 6-mercaptopurine;6-MP Mechanism:
it must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form (6-thioinosinic acid), which in turn inhibits a number of the enzymes of purine nucleotide interconversion
Indication：
1.AL：child AL
2. choriocarcinoma ：less than 5-FU, ACTD, MTX
3.Immunosuppresive agent：a closely related analog, azathioprine

17. cytarabin; AraC Mechanism： Indication： 1.Inhibitor of DNA polymerase
2.Incoporation into DNA，inhibition of DNA copy
Indication：
Acute Myeloid Leukemia , acute monocytic leukemia Induction Chemotherapy ，28％ alone

18. hydroxyurea；HU Mechanism： Indication： ↓ HU
ribonucleotide reductase inhibitor
cytidylate deoxycytidylate DNA, S phase
Indication：
1. chronic myelogenous leukemia ：>50％
2. Melenoma (12％)

19. 2. Disrupt the DNA stucture and function
2.1 alylating agents CH2
Mechanism：alkyl groups
active group( CH2-CH2- or N-CH2) binds to NH2, SH, OH, COOH or phpsphate, take place of H (alkylation)
Resulting in：
The major site of alkylation within DNA is the N7 position of guanine (covalent bond ).
(2) interactions can occur on a single strand or on both strands of DNA through cross-linking, leading to the disruption of DNA synthesis and cell death.

20. properties 1.CCNSA 2.Board spectrum Defects：
Low selection, severe toxicity to bone marrow, GI, reproductive system, liver and kidney.

21. nitrogen mustard properties： 1.rapid：iv 3 min
2.short：several min but long-acting

22. Indication 1.Malignant lymphoma：lymphosarcoma 、Hodgkin's Lymphoma
2. Hemi-body Irradiation ：nasopharyngeal carcinoma 、Lung cancer.
65～71％effictive in 1180 cases，5 years survival in 122 cases(10.33%)
Side effect：common and obvious(discussed previous)
tissue necrosis due to leak during IV

23. Cyclosphosphamide；CTX
Pharmacological action ：
CTX→phosphoramide→crosslinking with DNA
Characteristic：
1. Board spectrum
2. Chemotherapeutic index (CI) is bigger than most alkylating agents
3.Short period of high-dose or intermittent middle- dose treatment are better than prolonged low-dose treatment
4. po is effective

24. Indication：
1. Malignant lymphoma：lymphosarcoma 、Hodgkin‘s Lymphoma, Hemangioblastomas ，50~90％ effective
2.Ovarian cancer (44％)、breast cancer (32％)、Multiple Myeloma (29％)、seminoma (40％)
3. Acute lympocytic leukemia
4. Autoimmune disease : Effective in almost every type

25. Side effect 1. Myelosuppression 2. alopecia is common (30～60％)
3. hemorrhagic cystitis

26. Thio-TEPA Characteristics： 1.High selection、 board spectrum
2. Low irritation：can be administrated iA、iv、im and intra-thoracic,intra-abdominal, intravesikale
3.Less and mild gastrointestinal reaction

27. Indication
Breast cancer (30％)、 Ovarian cancer (31％), liver cancer、malignant melanoma 、lung cancer、gastric carcinoma 、cervical cancer 、nasopharyngeal carcinoma 、laryngo-carcinoma

28. Busulfan (Myleran)
Chronic Myelogenous Leukemia : effective in 80～90％cases，first choice.

29. (二)Antibiotics Mitomycin Pharmalogical action：
Cross linking with double-stranded DNA，non-specific interaction in cell cycle
Indication：
Breast cancer (34.7％)、 gastric carcinoma (26.9％) 、cancer of pancreas (20.8％)
biliary Tract Carcinomas （16.9％）、CML、 malignant lymphoma

30. Side effect 1. Myelosuppression: obvious and long-lasting
2. Cardiac toxicity：sudden occurrence of heart failure
3. Tissue necrosis due to leak
4. Renal toxicity

31. Bleomycin， Mechanism：break down DNA→interupt DNA duplication
indication：
1. squamous epithelial carcinoma 、cancer of the esophagus (30~50％ effective，first choice)、
head and neck cancer (20～55％)、cervical cancer
2. Cancer of the Testes ：can be completely cured when combined with DDPand VLB
Side effect：
pulmonary fibrosis : positive correlation with dose

32. (三) Drugs interrupted transcription and blocked RNA synthesize
Dactinomycin　
Mechanism:
Insert in guanin and cell pyrimidine of DNA and inhibit RNA polymerase→interupt mRNA synthesize

33. Indication Side effect：
1. choriocarcinoma and ovarian malignant mole ：50-70％ effective
2. nephroblastoma：cured in 80% cases by combination use of this drug with surgery and radiotherapy
3. malignant lymphoma 、neuroblastoma
Side effect：
Gastrointestinal reaction 、myelosuppression 、 alopecia 、foetal deformities

34. Doxorubicin，ADM Characteristics：broad spectrum、high efficiency
Indication：
Breast cancer(31～43％)、lung cancer (12～36％), osteosarcoma (30％)、Hodgkin's lymphoma、 gastric carcinoma 、liver cancer

35. Side effect Common: general toxicity
Rare: arrhythmia and heart failure
Total dose＜550 mg／m2

36. (四)、Drugs interupted protein synthesize
Vinblastin (VLB) and Vincristin (VCR)
Mechanism：combine with tublin → inhibit tublin assembling → block spindle fiber formation→ terminate mitosis

37. Indication： Side effect： VLB：acute leukemia、lymphoma、 ovarian cancer
VCR：AML、 Lymphoma (20％), breast cancer (20％)、lung cancer
Side effect：
VLB： obvious myelosuppression、 alopecia
VCR：light myelosuppression ，obvious peripheral neuritis

38. Taxol
Mechanism：promote tublin assembling, inhibit tublin depolymerization → block spindle fiber formation→ terminate mitosis
Indication：Ovarian cancer (＞30％)、breast cancer (50％), malignant melanoma 、gastrointestinal cancer 、leukemia

39. Principles of combination use
Objective：
1.Increase efficiency
2.Decrease drug resistant
3.Decrease toxicity

40. Principles: 1．Based on proliferation dynamics of tumor:
Solid tumors(robust cells in G0)：use cell cycle non-specific drugs first，then use specific drugs
Acute Leukemia：Contrary to solid tumor

41. 2. Based on mechanism of different drugs
Sequential inhibition：inhibition at different metabolic stage by combination of two or more drugs
e.g：
Hydroxyurea AraC
↓ ↓
　inhibit ribonucleotide inhibit DNA polymerase
reductase

42. (2) Complementary inhibition
Inhibit nucleic acid synthesize 　+
Directly interupt DNA repair　
e.g.
Adriamycin CTX
↓ ↓
Inhibit RNA synthesize interupt DNA duplication

43. 3. Based on toxicity
Avoid overlap of toxicity: ↑efficiency but not↑toxicity
e.g. drugs with obvious myelosuppression(most anti-cancer drugs)+ drugs with no or mild myelosuppression(prednisone、VCR、BLM)

44. 4. Based on distribution and metabolism of drugs
e.g ：VCR can decrease intracellular distribution of MTX, resulting in increased cellular concentration of MTX，thus combination use can increase efficiency

45. 5. Based on anti-cancer spectrum：
gastrointestinal cancer ：5-FU、Thio-Tepa、CTX、mitomycin etc.
squamous epithelial carcinoma ：BLM、MTX
sarcoma：CTX、ADM
6. Adminstrative strategy
Intermittent high-dose adminstration is priority.