Cardiac Interactions of New Adriamycin Analogs and Taxol

描述（由申请人提供）：紫杉醇（Taxol）和阿霉素（DOX，阿霉素）是用于治疗转移性乳腺癌的化疗药物。当单独使用时，它们产生30- 40%的响应率。当联合使用高剂量的DOX （450-550 mg/m2）时，反应率增加到85- 95%。这代表了肿瘤反应性的显著改善。然而，当联合使用时，紫杉醇增加了高剂量DOX的心脏毒性，50%的患者出现心功能异常，20%的患者出现充血性心力衰竭。相比之下，在没有紫杉醇的情况下，累积剂量450- 550mg /m2的DOX在不到5%的癌症患者中引起充血性心力衰竭。紫杉醇增加DOX诱导的心脏毒性，至少部分是通过增加DOX的心脏毒性C-13羟基代谢物阿霉素（DOXol）的形成和心脏组织浓度。Gem Pharmaceuticals最近开发并获得了DOX类似物（GPX-100和GPX-150）的专利，它们比DOX的心脏毒性更小，并且不会形成C-13羟基代谢物。因此，假设这些类似物与紫杉醇联合使用时不会对心脏产生毒性，同时保持协同抗肿瘤活性。这一假设将通过评估兔离体心房和乳头肌在不存在和不存在紫杉醇的情况下，暴露于DOX、GPX-100和GPX-150浓度下的收缩性、舒张性和依从性变化来验证。此外，紫杉醇活性增加DOX的心脏毒性（左心室分式缩短、孤立心房和乳头肌功能和组织病理学评分）。GPX-100和GPX-150将在兔体内静脉给药后测定。紫杉醇对心脏组织DOX、GPX-100、GPX-150和代谢物浓度的影响也将被确定。紫杉醇增强DOX、GPX-100和GPX-150抑制两种人乳腺癌细胞系（MCF-7和MDA-MB 231）增殖的活性也将被评估。如果这些类似物与紫杉醇协同抑制癌细胞生长，并在与紫杉醇联合使用时保持其非心脏毒性，那么它们与紫杉醇联合使用治疗转移性乳腺癌时可能比DOX提供更好的临床益处。因此，这些实验的结果将有助于Gem制药决定是否继续开发和商业化GPX-100和GPX-150与紫杉醇和其他紫杉醇联合治疗转移性乳腺癌。

DESCRIPTION (provided by applicant): 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.