????Anticancer drugs

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????Anticancer drugs
???????????????,??David E. Thurston,?????,???????
,2008 Tumor/neoplasm ????????????????,??????????
???????? Cancer ??/??????????????????????????????
Facts ??????? 1/3 ??????,???2200???,?????1000?
¼ ??????,????????????????????(metastasis) ??????,
10???/?/?(??) ???????????????????,unmet market
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• Oncogenes ????
• Tumor suppressor genes ??????,?p53
• Tumorigenesis ???,???????????,???/chromosomal
  translocations
• ????6???(Weinberg)
• ?????? / ?????????? / ???????? / ????????/
  ??????? / ???????

(Cell 2000 )
3
(Cell 2011)

• ??????
• ???DNA???(??,1940s)
• ????(????,1950s)
• ??????(???????,1990s)
• ??????(Gleevec,2000s)

???? ???? / DNA????? / ?????? / ????????? /
?? ????(EB) / ???? / ???? (???,??)/a, b,
g,X??,UVC
4
???????

• ?????DNA???
• ??? (??????????????????)
• ????
• DNA???????
• DNA????????
• 2. ?????
• 3. ?????
• 4. ??????

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1. ?????DNA???
??DNA?????????? (????,??) 1.1 ???
????????????????DNA????????? ???????????????,?DNA?
????????????,DNA? ??????????
1.1.1 Dacarbazine ??????
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Temozolomide(1990?)
???????????,?F, ???CNS,DNA???G???,??????CO2?N2????
???? DNA???,Mismatch repair enzymes(MMRs)???O6-M
eG-T,???????T,???T,????????????
(MMRs????????Temozolomide??) MMRs?????????O6-alky
lgunine-DNA-alkyltransferase,????O6?????????
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ET-743, Yondelis, ?????????? ??????(non
p53-dependent apotosis) ?TC-NER??,????????/ET-743/
DNA?????????DNA????,???????G2?DNA???? ??c-jun,
c-fos????? ????????????MDR1(multidrug resistance
gene, MDR1)??????
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1.1.2 ???
????????????DNA????,????/??????????? ???DNA??????
????DNA????,???????
Chlorambucil,????????Cl??,????,????
??chlormethine
???????,????,???????? ???,DNA??????
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????? ?????,???????,?????
Melphalan ???? ???????,???
Prednimustine(?????) ??????????????? ??????????,??
??
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Cyclophosphamide ????
????,??????,?pH4.0-6.0????????(???????Prodrug)
?????,??N?????,?????,??????????,????(???????) ????
?????,???
??????????
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??????
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1.1.3 ???? (?????)
Thiotepa ??,P450??
Diaziquone
??????????????? DNA??G?N2??????? ?????????????,??
????????????????,???,?????? ??????,?????????
????-C,Mitomycin-C 1958??Streptomyces
caespitosus???????????????
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1.1.4 ?????(???????)
???busulfan
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1.1.5 ?????(nitrosoureas)
Carmustine ???BBB,???? ?????,????????CO2 ????N????
??????????,?????????,DNA?????
lomustine
Ranimustine ???BBB,???????? ?????,?????,????
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1.2 ????
1960s????, Rosenberg??E-coli?????????????????,????
????????,????????
?????DNA???????????????,??DNA?,?DNA??,???DNA??,???
?
??Cisplatin ???,???????????,???????,???????????,?
????????,??170o?????,270o?? ???????????????59,???
30
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???????
??Carboplatin ???,???? ????????????? ????,???????
Oxaliplatin, ????????? ???????
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1.3 DNA???????
SJG-136 (Phase II,????) Pyrrolobenzodiazepine ???
SJG-136??????G?N2????,?DNA???????????????????,????
???,??DNA???????????
Bizelesin, SJG-136???,???????Cl????????? ???6 bp,
????DNA???A?N3??? ??????
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DNA???
??????,????????????,??DNA??,??????????????????????
???????????????????GC?? ??1??DNA,??DNA????? ??2?
?DNA??????,???? ??3?????,???????????,????????? ??
????????????????,??Ca2,Fe2, DNA?????,????
Doxorubicin????
Daunorubicin
Aclarubicin
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Idarubicin, the only oral/IV drug in
anthracyclines
epirubicin
???
Mitoxantrone, ??????GC DNA???
Dactinomycin????D
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Dactinomycin, ??????DNA GC ????DNA??
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DNA???
Fe(II)??????????????,???/????
??DNA,sulfonium??DNA?????
????/?DNA/??????
?????????????DNA,?DNA???
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1.4 DNA Topoisomerases inhibitors
DNA???????DNA??????????,???????DNA?????????DNA???,
??????,????????,?????
Topo I ?DNA?????????,Pi???Y??,????DNA?????,???????
Topo II??????DNA DNA????????,???DNA???/??,???????
??? ??????/??gtgt???? ??????
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Topo I inhibitors
???camptothecin Topo I inhibitor ????topo
I/DNA????? ?????????? ???,????
Topotecan, ??????????????? ????????,????S?
??
SN-38????2002000X
Irinotecan, ??,S?
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Topo II inhibitors
Podophyllotoxin???? ??mandrake????????
Etoposide ?????????,???? ??Topo IIa, Topo IIb
teniposide
Amsacrine ???/????doxorubicin