TITLE:
Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin Orotate
AUTHORS:
Rashida A. Karmali, Yulia Maxuitenko, Greg Gorman
KEYWORDS:
Safer Toxicity Profile, Doxorubicin Orotate
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.5,
April
23,
2014
ABSTRACT:
Background: Doxorubicin
(DOX) is an effective treatment for many cancers across the age spectrum, but
its therapeutic potential is limited because of dose-dependent relation to both
progressive and irreversible cardiomyopathy leading to congestive heart
failure. While decreases in cardiotoxicity have been reported with liposomal
doxorubicin, the long-term cardiac effects are not known. Orotate salts of
cytotoxic drugs have been shown to confer antitumor effects with a better
safety profile than unconverted drug, and therefore may offer an improved
approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted
CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt
(DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling
time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O
and liposomal doxorubicin formulations to determine DOX concentration in liver
and heart; and to evaluate their effect on body weight. Non-tumored female,
athymic NCr-nu/nu mice
were treated with daunorubicin and daunorubicin orotate to evaluate tolerance.
Results: DOX and DOX-O exhibited significant, similar levels of antitumor
activity. Mice treated with DOX-O had a lower percentage body weight loss. In
the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal
doxorubicin was associated with the lowest percentage of body weight loss, but
the highest concentration of DOX in heart. In daunorubicin tolerance
experiments, animals showed a better tolerance for daunorubicin orotate as
measured by a smaller percentage change in body weight. Conclusions: DOX-O is
effective as an antitumor therapy and may offer a less toxic alternative to DOX
for maintaining therapy. The lower percentage of body weight loss in animals
treated with DOX-O and daunorubicin orotate is a measure of improved tolerance
and may translate into better patient outcomes.