DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials.
The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.
Kratz
Felix
F
Macromolecular Prodrugs, Tumor Biology Center, Freiburg, Germany. felix@tumorbio.uni-freiburg.de
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*
D000418:Albumins; D000903:Antibiotics, Antineoplastic; D006835:Hydrazones; D011355:Prodrugs; C085780:doxorubicin(6-maleimidocaproyl)hydrazone; D004317:Doxorubicin; C575867:DOXO-EMCH