DHA结合紫杉醇靶向肿瘤。
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Bradley MO, Swindell CS, Anthony FH, Witman PA, Devanesan P, Webb NL, Baker SD, Wolff AC, Donehower RC
DHA结合紫杉醇靶向肿瘤。
中华医学杂志。2001年7月6日;74(1-3):233- 36。
- PubMed ID
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11489499 (PubMed视图］
- 摘要
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将一种抗癌药物靶向肿瘤，可以增加肿瘤内的药物浓度-时间曲线下面积(Area Under the drug concentration-time Curve, AUC)，同时降低正常细胞内的AUC，从而提高该药物的治疗指数。抗肿瘤药物的半衰期通常比大多数肿瘤细胞的细胞周期运输时间短得多。肿瘤靶向，伴随着较长的肿瘤暴露时间，当药物浓度高时，会增加进入周期的细胞比例，这应该会导致更多的肿瘤细胞死亡。为了验证这一假设，我们将一种天然脂肪酸二十二碳六烯酸(DHA)通过酯键与紫杉醇2′-氧结合。由此产生的紫杉醇脂肪酸缀合物(dha -紫杉醇)不组装微管，无毒。在M109小鼠肿瘤模型中，dha -紫杉醇的毒性小于紫杉醇，可治愈10/10的肿瘤动物，而紫杉醇可治愈0/10。一种解释是，脂肪酸改变了药物的药代动力学，增加了它在肿瘤中的AUC，降低了它在正常细胞中的AUC。为了验证这一可能性，我们比较了dha -紫杉醇和紫杉醇在CD2F1小鼠中承载约125 mg sc M109肿瘤的药代动力学。小鼠在零时注射dha -紫杉醇或10%甲酚/10%乙醇/80%生理盐水配制的紫杉醇。动物被作为时间的函数被牺牲，直到14天。 Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of paclitaxel derived from i.v. paclitaxel drops rapidly, so that by 16 h it has fallen to the same concentration (2.8 microM) as after an equi-toxic concentration of DHA-paclitaxel. In plasma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5% of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited plasma AUC of paclitaxel following DHA-paclitaxel administration are consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel in the M109 mouse tumor model. A phase I clinical study has been completed at The Johns Hopkins Hospital to evaluate the safety of DHA-paclitaxel in patients with a variety of solid tumors. Twenty-one patients have been treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar basis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primary side effect. Eleven of 22 evaluable phase I patients transitioned from progressive to stable disease, as assessed by follow-up CT. Significant quality of life improvements have been observed. Thus, DHA-paclitaxel is well tolerated in patients and cures tumors in mice by targeting drug to tumors.
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