MECHANISMS OF ACTION OF HIGHLY EFFICACIOUS PGA-TAXOL

紫杉醇（紫杉醇）已显示出对几种 包括乳腺癌在内的各种恶性疾病。 如同 然而，大多数化疗剂的最大剂量 紫杉醇受到毒性的限制。 在人类中，药物诱导的毒性是 表现为粒细胞减少和周围神经病变。 其他 紫杉醇临床应用的主要困难包括水溶性差 溶解性和耐药性。 高分子药物策略 已经尝试缀合以改善应用和功效 紫杉醇。 具体来说，一种高度水溶性的聚合物紫杉醇 结合物（PGA-紫杉醇），其在体内显示出显著的 在两种啮齿动物肿瘤模型中的抗肿瘤活性已经被开发出来。 大鼠肌内植入13762乳腺肿瘤 （约治疗时2400 mm 3），单次静脉注射 注射剂量为40 mg equiv.紫杉醇/kg体重 体重诱导肿瘤完全消退。 相比之下， 相同剂量的紫杉醇仅延迟肿瘤生长9天（vs. Cremophor媒介物处理的对照）。 此外，抑制 PGA-紫杉醇的肿瘤生长，实现了较低的毒性 比紫杉醇治疗产生的效果更差。 此外，PGA-紫杉醇显示出对紫杉醇耐药的活性， 肿瘤细胞，表明化疗药物的缀合 药物聚合载体可能是一个有用的策略，以克服 耐药性 为了更好地了解增强的抗肿瘤 PGA-紫杉醇和AID在未来设计中的功效， 用于选择性递送药物的聚合物药物载体的开发 化疗药物，重要的是要进一步研究 PGA-紫杉醇的药理学和毒理学性质。 这些 这些研究在计划未来的人体试验中也是至关重要的。 PGA-紫杉醇作为一种潜在的强大的抗癌剂。 的 该提案的具体目标是：（1）综合和 表征单体谷氨酸-紫杉醇缀合物和PGA- 不同分子量的紫杉醇偶联物;（2）研究它们的 体外细胞毒性和细胞蓄积动力学;（3） 检查PGA-紫杉醇是否具有独特的作用机制 与紫杉醇不同;（4）评价它们的毒性和体内毒性 在适当的肿瘤模型中的抗肿瘤活性;和（5）研究 其药代动力学、组织分布和肿瘤内 分布

Taxol (paclitaxel) has shown significant activity against several types of malignant diseases, including breast cancer. As with most chemotherapeutic agents, however, the maximal dose of taxol is limited by toxicity. In humans, drug-induced toxicity is manifest as granulocytopenia and peripheral neuropathy. Other major difficulties in the clinical use of taxol include poor aqueous solubility and drug resistance. A strategy of polymer-drug conjugation has been attempted to improve the utility and efficacy of taxol. Specifically, a highly water-soluble polymer-taxol conjugate (PGA-taxol) which has shown remarkable in vivo antitumor activity in two rodent tumor models has been developed. In rats bearing intramuscularly implanted 13762 mammary tumor (approx. 2400 mm3 at time of treatment), a single intravenous injection of PGA-taxol at a dose of 40 mg equiv. Taxol/kg body weight induced complete tumor regression. In comparison, the same dose of taxol delayed tumor growth only 9 days (vs. Cremophor vehicle-treated controls). Furthermore, the inhibition of tumor growth by PGA-taxol was achieved with less toxicity than that produced by the less effective taxol treatment. Additionally, PGA-taxol showed activity against taxol-resistant tumor cells, demonstrating that conjugation of chemotherapeutic drugs to polymeric carries may be an useful strategy to overcome drug resistance. To better understand the enhanced antitumor efficacy of PGA-taxol and aid in the future design and development of polymeric drug carriers for selective delivery of chemotherapeutic agents, it is important to investigate further the pharmacological and toxicological properties of PGA-taxol. These studies should also be crucial in planning future human trials of PGA-taxol as a potentially powerful anti-cancer agent. The specific aims of this proposal are (1) to synthesize and characterize monomeric glutamic acid-taxol conjugate and PGA- taxol conjugates of different molecular weights; (2) to study their in vitro cytotoxicity and cellular accumulation kinetics; (3) to examine whether PGA-taxol has a unique mechanism of action different from that of taxol; (4) to assess their toxicity and in vivo antitumor activity in appropriate tumor models; and (5) to study their pharmacokinetics, tissue distribution, and intratumoral distribution.