title: A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts.
abstract: OBJECTIVE
  Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11).
  
  
  METHODS
  A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs.
  
  
  RESULTS
  A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED(50)) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab.
  
  
  CONCLUSIONS
  It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.
authors.affiliation: Kamakura Research Laboratories, Pharmaceutical Research Department, Chugai Pharmaceutical Co. Ltd., Kajiwara, Kanagawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Endo
authors.forename: Masanori
authors.initials: M
authors.lastname: Miwa
authors.forename: Masako
authors.initials: M
authors.lastname: Ura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
authors.forename: Masao
authors.initials: M
authors.lastname: Tsukazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Niizuma
authors.forename: Takeshi
authors.initials: T
authors.lastname: Murata
authors.forename: Sawako
authors.initials: S
authors.lastname: Ozawa
authors.forename: Hitomi
authors.initials: H
authors.lastname: Suda
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Eitaro
authors.initials: E
authors.lastname: Nanba
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nagao
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility; D014867:Water; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C541284:CH 0793076; D004151:Dipeptides; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; D011355:Prodrugs; C558017:TP 300; D014867:Water; D000077146:Irinotecan; D000110:Acetylcholinesterase; D002166:Camptothecin