A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts
| Autor: | Eitaro Nanba, Mika Endo, Hiromi Tanimura, Jun Ohwada, Shunsuke Nagao, Hisafumi Yamada-Okabe, Hitomi Suda, Satoshi Niizuma, Kenji Taniguchi, Masao Tsukazaki, Nobuo Shimma, Kotaro Ogawa, Masako Ura, Yoko Miyazaki, Takeshi Murata, Sawako Ozawa, Masanori Miwa |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Mice Nude Antineoplastic Agents Pharmacology Toxicology Irinotecan Heterocyclic Compounds 4 or More Rings Capecitabine Mice Cell Line Tumor medicine Irinotecan Hydrochloride ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans heterocyclic compounds Pharmacology (medical) Prodrugs neoplasms Cisplatin biology Topoisomerase Water Drug Synergism Dipeptides Prodrug Xenograft Model Antitumor Assays Neoplasm Proteins Transplantation Oncology Solubility Drug Resistance Neoplasm biology.protein Acetylcholinesterase ATP-Binding Cassette Transporters Camptothecin medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 65(2) |
| ISSN: | 1432-0843 |
| Popis: | Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11). 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. 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/ED50) 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. It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins. |
| Databáze: | OpenAIRE |
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