Paclitaxel (Taxol) and doxorubicin (DOX, Adriamycin) are chemotherapeutic drugs used in treatment of metastatic breast cancer. When used individually, they produce a 30-40 percent response rate. When combined, using high doses of DOX (450-550 mg/m2), the response rate is increased to 85-95 percent. This represents a significant improvement in tumor responsiveness. However, when combined, paclitaxel increases the cardiotoxicity of high dose DOX and 50 percent of patients develop abnormal cardiac function and 20 percent develop congestive heart failure. In contrast, cumulative doses of 450-550 mg/m2 DOX, in the absence of paclitaxel, cause congestive heart failure in less than 5 percent of cancer patients. Paclitaxel increases DOX induced cardiotoxicity, at least in part, by increasing formation and cardiac tissue concentrations of doxorubicinol (DOXol), the cardiotoxic C-13 hydroxy metabolite of DOX. Gem Pharmaceuticals has recently developed and patented DOX analogs (GPX-100 and GPX-150) that are less cardiotoxic than DOX and do not form C-13 hydroxy metabolites. Thus, it is hypothesized that these analogs will be noncardiotoxic when combined with paclitaxel while retaining synergestic antineoplastic activity. This hypothesis will be tested by evaluating contractility, relaxation and compliance changes of isolated rabbit atria and papillary muscles exposed to concentrations of DOX, GPX-100 and GPX-150 in the absence and presence of paclitaxel. In addition, paclitaxers activity to increase cardiotoxicity (left ventricular fractional shortening, isolated atrial and papillary muscle function and histopathology scoring) of DOX. GPX-100 and GPX-150 will be determined in vivo following iv administration into rabbits. Effects of paclitaxel to alter cardiac tissue concentrations of DOX, GPX-100, GPX-150 and metabolites also will be determined. Activity of paclitaxel to enhance the potency of DOX, GPX-100 and GPX-150 to inhibit proliferation of two human breast cancer cell lines (MCF-7 and MDA-MB 231) also will be assessed. If these analogs are synergistic with paclitaxel to inhibit cancer cell growth and retain their non-cardiotoxic properties when combined with paclitaxel, they may provide a better clinical benefit than DOX when used with paclitaxel for treatment of metastatic breast cancers. Thus, the outcome of these experiments will help Gem Pharmaceuticals determine whether to continue to develop and commercialize GPX-100 and GPX-150 for treatment of metastatic breast cancer in combination with paclitaxel and other taxanes.
