Cancer therapeutic drugs. 1.At present, about 50% of patients with cancer can be cured, with chemotherapy contributing to cure in 10– 15% of patients.

Cancer therapeutic drugs

At present, about 50% of patients with cancer can be cured, with chemotherapy contributing to cure in 1015% 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.Introduction of cancer therapy

Problem exiting in anticancer drug1.Low efficacy to most of cancer2.Severe toxicity(1)Bone marrow suppresion(2)GI(3) alopecia(4)Hepatic and renal toxicity3.Resistance(1) Absence the response to first exposure, e.g. MM(2) Acquired resistance

Classification1. 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)

Classification2. 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)

Classification3. According to cell cycle specificity

CCNSA Alkylating agents: Antineoplastic antibiotics:

(2) CCSA: vinblastin M stage anti-metabolites S stage

Kinetics of cell proliferationTwo cell types

1.Proliferating cells: log formulation

Proliferating cell numberGrowth fraction = ( GF) total cell number

GF highearly. Acute leukemia, Hodgkin's disease, and choriocarcinomasensitive to antineoplastic agentsGF lowlate. Chronic leukamiasolid tumor, low sensitivity

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

Resistance1. Nature resistance2. Acquired resistance MDR (multidrug resistance) PDR (pleiotropic drug resistance) mutation the larger cancer the more possibility of resistance (times of division)

Antineoplastic agents1. 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 metabolitesresults ininhibition of DNA, RNA and protein synthesis

Common propertiesCCSA: S1.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-FUPharmacological action5-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-FUIndicationwidely used

choriocarcinoma first choice, ACTDcolorectal cancer, liver cancer (25%)head and neck (30%), ovary cancer,bladder cancer, thyroid cancerToxicity:MyelosuppressionGIbleeding diarrhea

MethotrexateMTXmechanism structure analogue of folic acid, dihydrofolate reductase inhibitor 1. FH2 FH4 dTMP DNA 2. purine nucleotides RNA, protein IndicationLeukemia, choriocarcinoma Side-effectsMucositis, DiarrheaBone marrow depression with leukopenia and thrombocytopenia

6-mercaptopurine;6-MPMechanism: 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

Indication1.ALchild AL2. choriocarcinoma less than 5-FU, ACTD, MTX3.Immunosuppresive agenta closely related analog, azathioprine

cytarabin; AraCMechanism1.Inhibitor of DNA polymerase2.Incoporation into DNAinhibition of DNA copy

Indication Acute Myeloid Leukemia , acute monocytic leukemia Induction Chemotherapy 28 alone

hydroxyureaHUMechanism HUribonucleotide reductase inhibitor cytidylate deoxycytidylate DNA, S phase

Indication1. chronic myelogenous leukemia >502. Melenoma (12)

2. Disrupt the DNA stucture and function2.1 alylating agents CH2Mechanismalkyl groups active group( CH2-CH2- or N-CH2) binds to NH2, SH, OH, COOH or phpsphate, take place of H (alkylation)

Resulting inThe 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.

properties1.CCNSA

2.Board spectrum

Defects Low selection, severe toxicity to bone marrow, GI, reproductive system, liver and kidney.

nitrogen mustardproperties1.rapidiv 3 min

2.shortseveral min but long-acting

Indication1.Malignant lymphomalymphosarcoma Hodgkin's Lymphoma2. Hemi-body Irradiation nasopharyngeal carcinoma Lung cancer. 6571effictive in 1180 cases5 years survival in 122 cases(10.33%)Side effectcommon and obvious(discussed previous) tissue necrosis due to leak during IV

CyclosphosphamideCTXPharmacological action CTXphosphoramidecrosslinking with DNACharacteristic1. Board spectrum2. Chemotherapeutic index (CI) is bigger than most alkylating agents3.Short period of high-dose or intermittent middle- dose treatment are better than prolonged low-dose treatment4. po is effective

Indication1. Malignant lymphomalymphosarcoma Hodgkins Lymphoma, Hemangioblastomas 50~90 effective2.Ovarian cancer (44)breast cancer (32)Multiple Myeloma (29)seminoma (40)3. Acute lympocytic leukemia 4. Autoimmune disease : Effective in almost every type

Side effect1. Myelosuppression2. alopecia is common (3060)3. hemorrhagic cystitis

Thio-TEPACharacteristics1.High selection board spectrum2. Low irritationcan be administrated iAivim and intra-thoracic,intra-abdominal, intravesikale 3.Less and mild gastrointestinal reaction

Indication Breast cancer (30) Ovarian cancer (31), liver cancermalignant melanoma lung cancergastric carcinoma cervical cancer nasopharyngeal carcinoma laryngo-carcinoma

Busulfan (Myleran)Chronic Myelogenous Leukemia : effective in 8090casesfirst choice.

()AntibioticsMitomycinPharmalogical action Cross linking with double-stranded DNAnon-specific interaction in cell cycleIndicationBreast cancer (34.7) gastric carcinoma (26.9) cancer of pancreas (20.8) biliary Tract Carcinomas 16.9CML malignant lymphoma

Side effect1. Myelosuppression: obvious and long-lasting2. Cardiac toxicitysudden occurrence of heart failure3. Tissue necrosis due to leak4. Renal toxicity

BleomycinMechanismbreak down DNAinterupt DNA duplicationindication1. squamous epithelial carcinoma cancer of the esophagus (30~50 effectivefirst choice) head and neck cancer (2055)cervical cancer 2. Cancer of the Testes can be completely cured when combined with DDPand VLBSide effectpulmonary fibrosis : positive correlation with dose

() Drugs interrupted transcription and blocked RNA synthesizeDactinomycinMechanism:Insert in guanin and cell pyrimidine of DNA and inhibit RNA polymeraseinterupt mRNA synthesize

Indication1. choriocarcinoma and ovarian malignant mole 50-70 effective2. nephroblastomacured in 80% cases by combination use of this drug with surgery and radiotherapy3. malignant lymphoma neuroblastomaSide effectGastrointestinal reaction myelosuppression alopecia foetal deformities

DoxorubicinADMCharacteristicsbroad spectrumhigh efficiencyIndicationBreast cancer(3143)lung cancer (1236), osteosarcoma (30)Hodgkin's lymphoma gastric carcinoma liver cancer

Side effectCommon: general toxicityRare: arrhythmia and heart failure Total dose550 mgm2

()Drugs interupted protein synthesize

Vinblastin (VLB) and Vincristin (VCR)

Mechanismcombine with tublin inhibit tublin assembling block spindle fiber formation terminate mitosis

IndicationVLBacute leukemialymphoma ovarian cancer VCRAML Lymphoma (20), breast cancer (20)lung cancer

Side effect

VLB obvious myelosuppression alopeciaVCRlight myelosuppression obvious peripheral neuritis

TaxolMechanismpromote tublin assembling, inhibit tublin depolymerization block spindle fiber formation terminate mitosis

IndicationOvarian cancer (30)breast cancer (50), malignant melanoma gastrointestinal cancer leukemia

Principles of combination useObjective

1.Increase efficiency2.Decrease drug resistant3.Decrease toxicity

Principles:1Based on proliferation dynamics of tumor:Solid tumors(robust cells in G0)use cell cycle non-specific drugs firstthen use specific drugsAcute LeukemiaContrary to solid tumor

2. Based on mechanism of different drugsSequential inhibitioninhibition at different metabolic stage by combination of two or more drugs e.g Hydroxyurea + AraC inhibit ribonucleotide inhibit DNA polymerase reductase

(2) Complementary inhibitionInhibit nucleic acid synthesize +Directly interupt DNA repair

e.g. Adriamycin + CTX Inhibit RNA synthesize interupt DNA duplication

3. Based on toxicityAvoid overlap of toxicity: efficiency but nottoxicitye.g. drugs with obvious myelosuppression(most anti-cancer drugs)+ drugs with no or mild myelosuppression(prednisoneVCRBLM)

e.g VCR can decrease intracellular distribution of MTX, resulting in increased cellular concentration of MTXthus combination use can increase efficiency4. Based on distribution and metabolism of drugs

5. Based on anti-cancer spectrumgastrointestinal cancer 5-FUThio-TepaCTXmitomycin etc.squamous epithelial carcinoma BLMMTXsarcomaCTXADM

6. Adminstrative strategyIntermittent high-dose adminstration is priority.