Heimberger A B, Archer G E, McLendon R E, Hulette C, Friedman A H, Friedman H S, Bigner D D, Sampson J H
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2000 Oct;6(10):4148-53.
Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.
脑内微量注射（ICM）是一种创新技术，可将治疗药物输送至大脑大部分区域，该技术可绕过血脑屏障，将全身毒性降至最低，并使注入药物均匀分布。替莫唑胺是一种新型甲基化剂，全身给药后对恶性胶质瘤（MGs）具有已证实的疗效，但存在剂量限制性骨髓毒性。由于MGs很少发生转移，因此无需进行全身药物递送。因此，我们在人MGs的无胸腺大鼠模型中评估了ICM联合替莫唑胺的疗效和毒性。在接种D54人MG异种移植物后3天，用替莫唑胺进行ICM治疗的大鼠，其生存期中位数比用生理盐水进行ICM治疗的大鼠延长了128%，比腹腔注射生理盐水的大鼠延长了113%，比腹腔注射替莫唑胺的大鼠延长了100%（P<0.001）。将治疗推迟至肿瘤接种后9天，与腹腔注射替莫唑胺的大鼠相比，用替莫唑胺进行ICM治疗的大鼠生存期中位数仍提高了23%。此外，总体而言，用替莫唑胺进行ICM治疗的大鼠中有21.7%存活超过100天，且无肿瘤的临床或组织学证据。本研究中通过ICM递送的替莫唑胺剂量仅受药物溶解度限制，且替莫唑胺ICM未导致任何神经或全身毒性。因此，替莫唑胺ICM在MGs治疗中可能具有显著优势。
