Cancer therapeutic drugs

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.

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

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)

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)

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

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↓

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

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)

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

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

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.

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

Methotrexate；MTX mechanism： structure analogue of folic acid, dihydrofolate reductase inhibitor 1. FH2 FH4 dTMP ↓ DNA ↓ 2. purine nucleotides↓ RNA, protein ↓ Indication：Leukemia, choriocarcinoma Side-effects： Mucositis, Diarrhea Bone marrow depression with leukopenia and thrombocytopenia

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

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

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

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.

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

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

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

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

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

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

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

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

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

(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

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

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

(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

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

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

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

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

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

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

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

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

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

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

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)

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

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.