抗肿瘤抗生素

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Chapter 7.3.Anticancer Antibiotics,抗,肿瘤抗生素,Anticancer antibiotics are drugs derived from microbial sources.,Dactinomycin,D,放线菌素,D(,更生霉素,),Mechanism of action:,DNA intercalation,Anthracyclines,蒽醌类,Daunorubicin,was isolated from,Streptomyces,coeruleorubidus,and,S.,peucetius,.,This significant discovery was made independently in France and Italy in 1963.,The most important member of the,anthracycline,doxorubicin(,adriamycin,)was isolated from,S.,peucetius,var.,caesius,in 1969 in Italy.,The history of doxorubicin can be traced back to the 1950s,when an,Italian,research company,Farmitalia,Research Laboratories,began an organized effort to find anticancer compounds from soil-based,microbes,.,Daunorubicin,was found first.,Researchers at,Farmitalia,later discovered A new strain of,Streptomyces,.This new strain produced a different,red-colored antibiotic.They named this new compound,Adriamycin,after the,Adriatic Sea,and the name was later changed to,doxorubicin.,Doxorubicin Hydrochloride,盐酸阿霉素,Mechanism of action:,Anthracyclines,inhibit,DNA,and,RNA,synthesis by,intercalating,between,base pairs,of the DNA/RNA strand,thus preventing the replication of rapidly-growing cancer cells.They also create iron-mediated,free oxygen radicals,that damage the DNA and cell membranes which also cause toxic side-effects.,Cartoon diagram of two doxorubicin molecules intercalating DNA,Clinical use:,Doxorubicin is one of the most effective anticancer agents.,It is effective for the treatment of acute,leukemias,Hodgkins disease and other lymphomas,Wilms,tumor,neuroblastoma,sarcomas,breast carcinoma,ovarian carcinoma,bladder carcinoma,and etc.,Major toxicity:,cardiotoxicity,Bleomycin,博莱霉素,(,争光霉素,),Bleomycin,is produced by the,bacterium,Streptomyces,verticillus,.,Bleomycin,refers to a family of structurally related compounds.When used as an anti-,cancer,agent,the chemotherapeutical forms are primarily,bleomycin,A2 and B2.The drug is used in the treatment of,Hodgkin lymphoma,squamou,cell,carcinomas,and,testicular cancer,pleurodesis,as well as,plantar warts,.,Bleomycin,was first discovered in 1962,when the Japanese scientist,Hamao,Umezawa,found anti-cancer activity while screening culture filtrates of,S.,verticullus,.,Umezawa,published his discovery in 1966.The drug was launched in Japan by Nippon Kayaku in 1969.,In the US,bleomycin,gained,Food and Drug Administration,(FDA)approval in July 1973,.,Bleomycin,acts by induction of,DNA,strand breaks.Some studies suggest that,bleomycin,also inhibits incorporation of,thymidine,into DNA strands.DNA cleavage by,bleomycin,depends on oxygen and metal ions,at least,in vitro,.It is believed that,bleomycin,chelates,metal ions(primarily iron)producing a,pseudoenzyme,that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA.,ET-743(,Yondelis,),is used for the treatment of soft tissue sarcoma.,DNA minor-groove binding drugs,Chapter 7.4.Plant products,抗肿瘤植物药,Vinca,Alkaloids and Their Analogues,Vinblastine,(,长春碱,),was first discovered when it was crushed into a tea.Consumption of the tea led to a,decreased number of white blood cells,;therefore,it was hypothesized that,vinblastine,might be effective against cancers of the,white blood cells,such as,lymphoma,.It is an,anti-mitotic,drug,used to treat certain kinds of,cancer,including,Hodgkins lymphoma,non-small cell,lung cancer,breast cancer,and,testicular cancer,.,Vincristine,长春新碱,Camptothecin,喜树碱,CPT,was isolated from a Chinese tree,Camptothecca,acuminata,in 1966 by Wall et al at the Southern Research Institute in the US.CPT is not used in clinic because of toxicity.,10-hydroxycamptothecin(HCPT),was also isolated from,Camptothecca,acuminata,and is used in China an,an,anticancer drug.,Camptothecin,(CPT),10-hydroxycamptothecin(HCPT),CPTs,act by inhibiting,topoisomerase,I,an enzyme which plays a key role in maintaining the structure of DNA during translation,transcription,and replication.,Topoisomerase,I solves the problem caused by tension generated by winding/unwinding of DNA.,It wraps around DNA and makes a cut permitting the helix to spin,.Once DNA is relaxed,topoisomerase,reconnects broken strands.,When,camptothecin,binds to,topoisomerase,I,it will be able to cleave but not to,religate,DNA.Thereby,camptothecin,causes single strand breaks in DNA.,Mechanism of action of,CPTs,Topotecan,(,Hycamtin,),is used to treat,ovarian cancer,and,lung cancer,as well as other cancer types,Irinotecan,is mainly used for the treatment of,colon cancer,particularly in combination with other chemotherapy agents.This includes the regimen,FOLFIRI,which consists of,infusional,5-fluorouracil,leucovorin,and,irinotecan,.,Irinotecan,was first introduced in Japan by the Pharmaceutical arm of,Yakult Honsha,as,Campto,.In 1994,it received accelerated,FDA,approval in the United States,where it is now marketed by,Pfizer,as,Camptosar,.It is also kn