The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Abstract

Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the longterm and explain in part the delayed onset of heart dysfunction. DOXO-EMCH a 6-maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, we examined the chronic cardiotoxicity of DOXO-EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO-EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO-EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c-oxidase (COX, 26% of controls), reduced expression of the mtDNA-encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO-EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high-dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin-exposed hearts and to a lesser extent the myocardia of both DOXO-EMCH groups contained mtDNA-deletions. In summary both DOXO-EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX-activity, COX II expression, mtDNA-content, mtDNA mutation loads and superoxide production in rats. ' 2006 Wiley-Liss, Inc.Key words: doxorubicin prodrug; mitochondria cytochrome oxidase; DNA mitochondrial; reactive oxygen species Doxorubicin is an antineoplastic anthracycline that is widely used in the treatment of leukemia and lymphoma, breast and ovarian carcinoma and many other solid tumors. Bone marrow suppression with maximum toxicity after 7-10 days and a rapid recovery thereafter generally limits the escalation of single doses. Cumulative doses of doxorubicin exceeding 500 mg/m 2 in contrast, are curtailed by a late-onset and irreversible cardiotoxicity. The antitumor potency and toxicological profile of anthracyclines has been the impetus for a diligent search for more effective and less toxic anthracycline analogues, and 2,000 derivatives have been developed during the past 20 years.2 Despite these efforts, daunorubicin, epirubicin, idarubicin, pirarubicin, zorubicin, aclarubicin and carminomycin have not satisfactorily improved the therapeutic index of anthracyclines in clinical practice. 3To improve the therapeutic potential of doxorubicin, we have developed a macromolecular prodrug in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule (i.e., 6-maleimidocaproyl ...

Anti-Myeloma Effects of the Novel Anthracycline Derivative INNO-206

“…In contrast, doxorubicin administered at 4.0 and 8.0 mg/kg, using the same schedule and route of injection as INNO-206, resulted in deaths in all animals by day 42. Other laboratories have shown that INNO-206 is superior to doxorubicin with respect to reducing cardiotoxicity and mitochondrial damage at equimolar as well as equitoxic doses in a rat model (42), and significantly lower levels of INNO-206 were observed in the heart, liver, and kidneys of mice when compared with similar studies assessing doxorubicin (21). The lack of deaths observed in our in vivo study with INNO-206 is consistent with a favorable shift in the lethal dose, which is 2-to 5-fold higher for INNO-206 compared with free doxorubicin (37,43).…”

INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model

“…INNO-206 was selected as the investigational product for clinical evaluation after toxicology studies in mice, rats, and dogs had shown a two-to fivefold increase in the maximum tolerated dose (MTD) when compared to conventional doxorubicin and a better tolerability in a four-cycle study in rats and a two-cycle study in dogs even at a threefold higher dose for INNO-206 than for doxorubicin [14]. INNO-206 has also shown significantly less chronic cardiotoxicity at equimolar as well as equitoxic doses compared to doxorubicin in a rat model [15].…”

Role of mtDNA lesions in anthracycline cardiotoxicity

“…3) [46,47]. Due to its maleimide group DOXO-EMCH binds quantitatively and selectively to the cysteine-34 position of albumin after intravenous administration.…”