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AntiCancer Drugs II
Stack #76925
Question | Answer |
---|---|
DNA-trageting antitumor antibiotics from streptomyces | bleomycins, dactinomycin, anthracyclines, mitomycin C |
Bleomycin (general) | glycopeptide, naturally cu comples but act as fe complex, inhibit DNA repair |
DNA-trageting antitumor antibiotics from streptomyces | bleomycins, dactinomycin, anthracyclines, mitomycin C |
Bleomycin (general) | glycopeptide made by S. verticillus, naturally cu comples but act as fe complex, inhibit DNA repair |
Bleomycin (structure) | 4 aromatic heterocycles; pyrazine and imidazole rings chelate with Cu/Fe; Thiazole rings (S) bind DNA; L-surgar residues are cell recognition and uptake site; terminal amide is the metabolic site |
Bleomycin (MOA) | Form 5-cooridinated Fe (II) complexes (5 bonds to N, 1 to O); O is reduced to hydroxyl radical which reacts with DNA |
Bleomycin (application) | Carcinomas: Testicular, squamous cell, ovarian germ cell, lymphoma, cervix, head, neck, larynx |
Bleomycin (toxicity) | pnuemonitis, pumonary fibrosis |
Dactinomycin = actinomycin | produced by S. parvulus; tricyclic core is a 3-phenoxazone-1,9dicarboxylate |
Dactinomycin (substituents) | contains 2 pentapeptide rings; aa in each ring: Thr-MeVal-MeGly(SAR)-LPro-DVal-back to L Thr |
Dactinomycin (MOA) | tricyclic phenoxazone ring intercalates b/w base pairs; the aromatic rings undergo Pi-Pi stacking; causes local distorating and interferes with TopoIsomerase II; DNA replication and transcription is impossible |
Dactinomycin (Use/Shortcoming) | Rhabdomyosarcomas; Wilms tumor/ does not cross BBB |
Anthracyclines | Daunorubicin, Doxorubicin, Idarubicin, Epirubicin, and Valrubicin |
Anthracyclines (general) | most studied class of antitumor drugs; tetracycli anthraquinone aglycon and a unique amino-surgar; intercalate into DNA--inhibit Topoisomerase II; used in many multi-drug regimens |
Daunorubicin/Doxorubicin | original natural products of S. peucetius; doxorubicin has an OH in 14 position |
Idarubicin | synthetic daunomycin analogue (no 4-OCH3 gp); improved cellular uptake and prolonged half-life |
Valrubicin | semisynthetic derivative of doxorubicin (12-o-valerylester); used for tx of BCG refaractory urinary bladder carcinoma |
Epirubicin | originally doxorubicin derivative--now can be made by bacteria; structurally the same as doxorubicin except 4-OH is equatorial; reduced toxicity, adjuvant for axillary node tumor tx |
ANthracyclines (MOA) | amino surgar binds to phosphate backbone; intercalation leads to DNA breaks due to repair attempts of TI II and generation of ROS (reactive oxygen species); ROS contributes to cardiac toxicity |
Anthracycline (application) | IV only; used in coctails, doxorubicin and derivitives have broader applications |
Daunorubicin (application) | acute leukemias, Kaposi sarcoma; applied as HCl or citrate liposomal product; metabolism: keto gp reduction/ loss of surgar moiety/demethylation followed by glucuronidation |
Doxorubicin (application) | acute leukemias, solid tumors, hodgkins disease, lymphoma, lung carcinoma, various sarcomas, applied as HCl or liposomal product (DOXIL) |
Mitomycin C (structure and use) | from S. caespitosus, "bioreductive alkylating agent"; used to tx pancreatic, intravesicular bladder, colon, and stomach cancer |
Mitomycin C (MOA) | solid tumors are hypoxic, under these conditions the quinone is reduced to hydroquinone -- a cascade of rxns follows leading to DNA crosslinking; contains aziridine ring -key to DNA alkylation |
Antitumor alkaloids from plants | Camptothecins, Vinca Alkaloids, Taxanes |
Camptothecins (general) | from C. acuminatat; natural product is too toxic; 2 semi-synthetic derivitives are more water soluble: topotecan and irinotecan; inhibits resealing reaction by TI I; used for colorectal, ovarian, and lung cancers |
Camptothecins (structure) | Pentacyclic structure with 1 chiral C at C-20; S isomer 100x more reactive than R-isomer; Rings: quinoline (2), pyran, 2-pyridone, and lactone (C-20); lactone ring opening a physiologic pH inc. water sol. |
Topotecan (use) | HCl salt, used mainly against metastatic ovarian cancer |
Irinotecan (structure/use) | HCl salt; carbamate prodrug activated by carboxylesterase (active metabolite=SN-28); 1000x more potent; used against metastatic colorectal cancer |
topoisomerase I activity | uncoil DNA for transcription; Tyr residue covalently binds 3-PO4 end of DNA breaking the strand; reseals after transcription |
Camptothecin (MOA) | stabilize the transiet topo I-DNA complex therefore inhibited religation; S-phase specific drugs |
Vinca alkaloids | from C. roseus; include vincristine, vinblastine, vindesine, vinorelbine |
Vinca (MOA and Use) | binds to tubulin causing depolymerization -- metaphase arrest; used for testicular tumors, lymphomas, breast and lung cancer, pediatric leukemia, wilms tumor and rhabdomycosarcoma |
Vinca (toxicity) | interferes with processes dependent on microtubular integrity ie.insulin and T-4 release; neuropathy occurs with vincristine |
Vinca (structure) | multicyclic asymmetrical dimeric structures with indole derived core; tertiary amines allow salt formation |
Taxanes (general) | from T. brevifolia; includes paclitaxel and docetaxel |
Taxane (MOA and Use) | binds tubulin but promotes microtubule formation in a wrong way-- mitotic arrest; used for tx of metastatic ovarian and breast cancer |
Pacitaxel (structural characteristics) | diterpenoid containing a complex tetracyclic taxane ring and an phenylalanine derived side chain/ very lipophilic, doesn't form salts, IV only, metabolized to 6-OH paclitaxel and dihydroxypaclitaxel by CYP450 oxygenase |
Docetaxel (taxotere) (structural characteristics) | core from T. baccata with synthetic t-butylcarbamate side chain |
Taxane (biosynthesis) | terpene core is synthesized from IPP, DMAPP, and GGDP, key enzyme=taxadiene synthase; DMAPP and IPP are synthesized by a "nonmevalonoid" pathway that starts with pyruvate nad hydroxyacetone phosphate |
MDR against natural anticancer drugs | decreased uptake, elevated metabolic enzymes |
MDR | tumor cells can become resistent to drugs with different MOA--overproduce P-glycoprotein pumps, mutant topoisomerase; drugs that overcome MDR: verapamil, cyclosporin, calmodulin inhibitors, quinolines |