Jackson J K, Gleave M E, Yago V, Beraldi E, Hunter W L, Burt H M
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Cancer Res. 2000 Aug 1;60(15):4146-51.
Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmetastatic human prostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a blend of a biodegradable triblock copolymer of a random copolymer of D,L-lactide and epsilon-caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 microl of this paste at room temperature. Changes in tumor progression were assessed using both serum prostate-specific antigen (PSA) levels and tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentration-dependent fashion with an IC50 of 1 nM. Apoptosis was documented using DNA fragmentation analysis. The paste formulation solidified over a period of 1 h both in vivo and in aqueous media at 37 degrees C as the methoxypoly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant released drug at a rate of about 100 microg/day in vitro. In control mice treated with paste without paclitaxel, serum PSA levels increased from 2-8 ng/ml (mean, 4.3+/-2 ng/ml) to 60-292 ng/ml (mean, 181+/-88 ng/ml), and tumor volume increased from 30 to 1000 mm3. In mice treated with a single 100-microl injection 3 weeks after castration (early-phase treatment group), tumors decreased in volume from a mean of 43+/-19 mm3 to nonpalpable, and PSA levels decreased from a mean of 22+/-8 to 2+/-1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after castration (androgen-independent tumors; late-phase treatment group), tumors decreased in volume from a mean of 233+/-136 mm3 to nonpalpable, and serum PSA decreased from 24+/-8 to 9+/-4 ng/ml. Observed side effects of the treatment were limited to minor ulceration at the needle injection site in paclitaxel-treated mice only. The controlled-release formulation can be injected via 22-gauge needles and is effective in inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple nonmetastatic tumors. Paclitaxel may be an effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment.
大多数因前列腺癌前来诊所就诊的患者，其肿瘤要么处于局部阶段，要么是放疗后复发的肿瘤，这些肿瘤可能适合采用缓释细胞毒性药物进行注射治疗。本临床前研究的目的是设计一种用于瘤内注射的紫杉醇可注射聚合物糊剂制剂，用于注射到在小鼠皮下生长的非转移性人前列腺肿瘤中。将紫杉醇（10% w/w）溶解在由D,L-丙交酯和ε-己内酯的无规共聚物（PLC）与聚乙二醇[PEG；PLC-PEG-PLC]组成的可生物降解三嵌段共聚物与甲氧基聚乙二醇按40:60比例混合而成的混合物中。在去势的无胸腺雄性小鼠皮下生长的人前列腺LNCaP肿瘤在室温下注射100微升这种糊剂。使用血清前列腺特异性抗原（PSA）水平和肿瘤大小评估肿瘤进展的变化。紫杉醇在体外以浓度依赖的方式抑制LNCaP细胞生长，IC50为1 nM。使用DNA片段化分析记录细胞凋亡情况。由于甲氧基聚乙二醇成分从不溶性PLC-PEG-PLC/紫杉醇基质中析出，该糊剂制剂在体内和37℃的水性介质中均在1小时内固化。该半固体植入物在体外以约100微克/天的速率释放药物。在用不含紫杉醇的糊剂治疗的对照小鼠中，血清PSA水平从2 - 8 ng/ml（平均，4.3±2 ng/ml）增加到60 - 292 ng/ml（平均，181±88 ng/ml），肿瘤体积从30立方毫米增加到1000立方毫米。在去势后3周接受单次100微升注射治疗的小鼠（早期治疗组）中，到去势后8周时，肿瘤体积从平均43±19立方毫米减小到无法触及，PSA水平从平均22±8降至2±1 ng/ml。在去势后5周接受治疗的小鼠（雄激素非依赖性肿瘤；晚期治疗组）中，肿瘤体积从平均233±136立方毫米减小到无法触及，血清PSA从24±8降至9±4 ng/ml。观察到的治疗副作用仅限于仅在接受紫杉醇治疗的小鼠的针头注射部位出现轻微溃疡。该控释制剂可通过22号针头注射，并且在抑制携带多个非转移性肿瘤的小鼠的LNCaP肿瘤生长和PSA水平方面有效。紫杉醇可能是放疗后局部肿瘤复发患者以及一些不适合进行根治性治疗的局部肿瘤患者的有效治疗方法。
