Ability of ribonucleotide reductase inhibitor and free radical scavenger Didox to protect against Doxorubicin mediated cardiotoxicity with enhanced antitumor activity
Authors: Ryan Sumpter, Waleska Cancel, Peter Loga, Oliver Oakley, Vincent S. Gallicchio, Arturo Cardounel, Cristian Dumitrescu, Jon Henry, Edy Tiravanti, Jay L. Zweier, Gustavo Loayza, Howard L. Elford
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2004 

Doxorubicin (DOX) is a leading member of the class of anthracyclines, antitumor drugs widely used against solid and hematological cancers, especially in breast cancer. Long term cardiomyopathy hinders clinical use of anthracyclines. The total dosage of anthracyclines in treatment protocols is limited because of this concern. According to the prevailing hypothesis, anthracyclines injure the heart by generating damaging free radicals through iron-catalyzed redox cycling. Didox is a potent ribonucleotide reductase (RR) inhibitor that possesses free radical scavenging and iron chelating properties while exhibiting anti-cancer activity on its own. We have assessed the cardioprotective effects of Didox, both acutely and chronically in the rat, using a Langendorff model of heart perfusion. In earlier acute experiments, the following treatments were studied after 30 min infusion: DOX, DOX + Didox, and Didox alone. Cardiac function, as measured by Rate Pressure Product (RPP), was reduced 40% by DOX alone, but was ameliorated with Didox infusion. Free radical presence, as measured by EPR spin trapping, showed that Didox treatment decreased the DOX-induced DMPO-OH signal intensity by greater than 80%. These results indicate that Didox offers cardioprotection against DOX mediated injury through its ability to scavenge free radicals. Chronic DOX toxicity studies were performed by weekly single dose i.v. injections of DOX or DOX + Didox. The progression of cardiomyopathy was monitored using echocardiography. Following 8 wks of treatment DOX treated animals demonstrated marked cardiomyopathy as evidenced by fractional shortening. The animals were then sacrificed and the cardioprotective effects of Didox assessed by measuring functional and histological parameters. Chronic administration of DOX resulted in greater than 50% decrease in left ventricular function as measured by RPP, but Didox offered 42% restoration. Additionally, we examined the effect of Didox and the classical RR inhibitor, hydroxyurea, as well as Zinecard, the iron chelator used clinically, to protect against cardiotoxicity in the mammary (16/c) mouse tumor model singly and in combination with DOX. Both DOX and the RR inhibitors had antitumor activity when used alone, producing a modest increase in survival over the untreated group. However, when DOX was combined with the RR inhibitors there was a significant (greater than additive) enhancement of the antitumor activity. These results further support our premise that a free radical scavenger can be used in conjunction with DOX and not impede its antitumor activity, and Didox may even enhance it. Therefore this drug would be a valuable addition to combination cancer treatment protocols that contain an anthracycline such as DOX.