ACTIVITY OF TOPOTECAN, A NEW TOPOISOMERASE-I INHIBITOR, AGAINST HUMAN TUMOR COLONY-FORMING-UNITS INVITRO
ACTIVITY OF TOPOTECAN, A NEW TOPOISOMERASE-I INHIBITOR, AGAINST HUMAN TUMOR COLONY-FORMING-UNITS INVITRO
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DOI：
10.1093/jnci/84.23.1816
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发表时间：
1992-12-02
期刊：
影响因子：
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通讯作者：
VONHOFF, DD
中科院分区：
文献类型：
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作者：
BURRIS, HA;HANAUSKE, AR;VONHOFF, DD
背景：Topotecan[(S)-9-dimethylaminomethyl(10-hydroxycamptothecin)，NSC 609699，SK&F 104864A]是天然产物喜树碱的半合成类似物，是一种细胞周期特异性药物，通过抑制拓扑异构酶I发挥抗肿瘤活性。目前，拓扑替康正在进行I期和早期II期临床试验。拓扑替康的限量毒性是骨髓抑制。目的：我们的目的是在拓扑替康的II期临床研究中，确定最佳临床活动性和肿瘤类型所需的血药浓度和暴露时间。方法：采用软琼脂克隆系统法检测拓扑替康对结直肠癌、乳腺癌、肺癌、卵巢癌、肾癌、胃癌及原发癌细胞的体外杀伤作用。我们研究了141个新鲜移植的肿瘤标本，使用拓扑替康1小时，80个使用持续暴露。如果集落存活率达到对照组的50%，则药物暴露导致的肿瘤集落形成减少被认为是体外反应。结果：在终浓度分别为1.0和10.0µg/mL的可评估肿瘤标本中，暴露1小时后，分别有10%和25%的肿瘤标本有体外反应。0.1和1.0µg/m L连续暴露，体外应答率分别为34%和76%。对结直肠癌、乳腺癌、非小细胞肺癌、卵巢癌和肾癌有一定的抑制作用，在可评估的肿瘤标本中，分别有27%、25%、32%、39%和83%的受试者在连续暴露于0.1mug/mLTopotecan后有反应。对阿霉素或氟尿嘧啶耐药的一组肿瘤标本对拓扑替康敏感，敏感性差异有统计学意义。此外，部分对环磷酰胺和依托泊苷耐药的肿瘤标本也对拓扑替康敏感。结论：拓扑替康在体外似乎对多种人类肿瘤具有活性，包括体外对标准抗肿瘤药物耐药的亚群。如果在正在进行的临床试验中，能在较长时间内达到0.1微克/毫升的血药浓度，拓扑替康应该会有很大的临床活性。提示：拓扑替康的进一步临床开发是有必要的。
Background: Topotecan [(S)-9-dimethylaminomethyl(10-hydroxycamptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. Purpose: Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. Methods: A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. Results: With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 mug/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 mug/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 mug/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. Conclusions: Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 mug/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. Implications: Further clinical development of topotecan is warranted.