Valrubicin is currently FDA-approved for intravesicular use against superficial bladder cancer (marketed by Endo Pharmaceuticals).
The pursuit of new applications for valrubicin has led to our discovery that this agent synergizes with ionizing radiation (IR). Preliminary studies from our research team indicate that low-dose, sub-cytotoxic valrubicin synergizes with low-dose, sub-cytotoxic IR to achieve persistent G2/M blockade in vitro in human squamous carcinoma cells and growth arrest in vivo of intrinsic oral tumors initiated in hamster cheek pouches. Further, the combined effect of valrubicin and IR does not appear to be due to detectable DNA fragmentation, suggesting a novel, non-nuclear mechanism of radiation enhancement. While the valerate side chain is susceptible to hydrolysis, resulting in the generation of N-trifluoroacetyladriamycin (AD 41), a mixed topoisomerase I/II inhibitor, analyses with the hydrolysis-resistant N-Trifluoroacetyladriamycin-14-pivalate (AD 36) confirms that synergy with IR is due to the parent compound. AD 36 and the newly developed AD 447 are under proprietary development by Paradox Pharmaceuticals, Inc. as radiation-enhancing agents. We believe that this class of anthracyclines can satisfy an unmet clinical need for effective radiation enhancing agents: 1) through efficient delivery of a non-contact toxic lipophilic drug directly to the tumor site coupled with rapid drug permeation into the tumor cells and 2) with drugs that are intrinsically less toxic to normal tissue but whose mechanism of action potentiates IR therapeutic effects. Benefits to patients would include more effective control of tumor and reduction in severe and often irreversible short and long-term adverse effects produced by high-dose IR.
no cumulative cardiotoxicity
no contact toxicity following administration into body cavities or inadvertent venous extravasation
reduced gastrointestinal toxicity and alopecia than comparable doses of doxorubicin.
Valrubicin exemplifies the successful clinical development by members of the Paradox Pharmaceuticals scientific team (Drs. Mervyn Israel and Trevor Sweatman, in association with Anthra Pharmaceuticals, Inc.) of anthracyclines that are functionally distinct from and superior to doxorubicin and daunorubicin. In pre-clinical studies, valrubicin enters cells more rapidly than doxorubicin, resulting in more extensive solid tumor penetration. The mechanism of action of valrubicin, while still not fully elucidated, is restricted to the cytoplasm, producing G2/M blockade and cell death following marked inhibition of DNA and RNA synthesis, but without direct nuclear DNA interaction and topoisomerase II inhibitory activity. In vivo pre-clinical analyses have shown that valrubicin is superior to doxorubicin in the control of hematologic tumors as well as lung tumors, osteosarcoma and melanoma. Unlike doxorubicin and daunorubicin, systemically administered valrubicin demonstrates: