Olivi A, Gilbert M, Duncan K L, Corden B, Lenartz D, Brem H
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Cancer Chemother Pharmacol. 1993;31(6):449-54. doi: 10.1007/BF00685034.
Platinum drugs are playing an increasingly major role in cancer treatment, but systemic administration of these agents has resulted in significant toxicity. To examine the effects of cisplatin and two newer agents, iproplatin and carboplatin, we injected the agents directly into the cerebrospinal fluid of rats and found that neurotoxic reactions resulted from doses of cisplatin (10 nmol) much lower than those of iproplatin (40 nmol) or carboplatin (80 nmol). Moreover, central nervous system tissue appeared to be less adversely affected by direct exposure to carboplatin since chronic toxicity was not observed in any of the animals receiving carboplatin until a lethal dose was reached. Furthermore, only the animals receiving cisplatin showed histologic damage in their spinal cords, and ultrastructural studies confirmed that while significant abnormalities were observed in the spinal cords of rats receiving 40 nmol cisplatin, no architectural changes were detected in the spinal cords of animals receiving 240 nmol carboplatin. We conclude that platinum drugs can be delivered intrathecally to achieve a much greater concentration of active drug than can be achieved by intravenous administration and that carboplatin appears to be the most suitable platinum-based drug for use in systems delivering drugs directly to the brain and spinal cord.
铂类药物在癌症治疗中发挥着越来越重要的作用，但全身给药这些药物会产生显著的毒性。为了研究顺铂以及两种新型药物异环磷铂和卡铂的效果，我们将这些药物直接注射到大鼠的脑脊液中，发现导致神经毒性反应的顺铂剂量（10纳摩尔）远低于异环磷铂（40纳摩尔）或卡铂（80纳摩尔）。此外，中枢神经系统组织似乎受直接接触卡铂的不利影响较小，因为在接受卡铂的任何动物中，直到达到致死剂量才观察到慢性毒性。此外，只有接受顺铂的动物脊髓出现组织学损伤，超微结构研究证实，接受40纳摩尔顺铂的大鼠脊髓中观察到明显异常，而接受240纳摩尔卡铂的动物脊髓未检测到结构变化。我们得出结论，铂类药物可以鞘内给药，以达到比静脉给药更高的活性药物浓度，并且卡铂似乎是最适合直接向脑和脊髓给药的基于铂的药物。
