Cao Shousong, Durrani Farukh A, Rustum Youcef M
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 2004 Apr 1;10(7):2561-9. doi: 10.1158/1078-0432.ccr-03-0268.
Studies were carried out in athymic nude mice bearing human squamous cell carcinoma of the head and neck (FaDu and A253) and colon carcinoma (HCT-8 and HT-29) xenografts to evaluate the potential role of selenium-containing compounds as selective modulators of the toxicity and antitumor activity of selected anticancer drugs with particular emphasis on irinotecan, a topoisomerase I poison.
Antitumor activity and toxicity were evaluated using nontoxic doses (0.2 mg/mouse/day) and schedule (14-28 days) of the selenium-containing compounds, 5-methylselenocysteine and seleno-L-methionine, administered orally to nude mice daily for 7 days before i.v. administration of anticancer drugs, with continued selenium treatment for 7-21 days, depending on anticancer drugs under evaluation. Several doses of anticancer drugs were used, including the maximum tolerated dose (MTD) and toxic doses. Although many chemotherapeutic agents were evaluated for toxicity protection by selenium, data on antitumor activity were primarily obtained using the MTD, 2 x MTD, and 3 x MTD of weekly x4 schedule of irinotecan.
Selenium was highly protective against toxicity induced by a variety of chemotherapeutic agents. Furthermore, selenium increased significantly the cure rate of xenografts bearing human tumors that are sensitive (HCT-8 and FaDu) and resistant (HT-29 and A253) to irinotecan. The high cure rate (100%) was achieved in nude mice bearing HCT-8 and FaDu xenografts treated with the MTD of irinotecan (100 mg/kg/week x 4) when combined with selenium. Administration of higher doses of irinotecan (200 and 300 mg/kg/week x 4) was required to achieve high cure rate for HT-29 and A253 xenografts. Administration of these higher doses was possible due to selective protection of normal tissues by selenium. Thus, the use of selenium as selective modulator of the therapeutic efficacy of anticancer drugs is new and novel.
We demonstrated that selenium is a highly effective modulator of the therapeutic efficacy and selectivity of anticancer drugs in nude mice bearing human tumor xenografts of colon carcinoma and squamous cell carcinoma of the head and neck. The observed in vivo synergic interaction is highly dependent on the schedule of selenium.
在携带人头颈鳞状细胞癌（FaDu和A253）及结肠癌（HCT - 8和HT - 29）异种移植瘤的无胸腺裸鼠中开展研究，以评估含硒化合物作为特定抗癌药物毒性和抗肿瘤活性的选择性调节剂的潜在作用，尤其着重于拓扑异构酶I抑制剂伊立替康。
使用无毒剂量（0.2毫克/小鼠/天）和给药方案（14 - 28天）的含硒化合物5 - 甲基硒代半胱氨酸和硒代 - L - 蛋氨酸，在静脉注射抗癌药物前，每天给裸鼠口服7天，并根据所评估的抗癌药物持续硒治疗7 - 21天。使用了几种剂量的抗癌药物，包括最大耐受剂量（MTD）和毒性剂量。尽管评估了许多化疗药物受硒的毒性保护情况，但抗肿瘤活性数据主要是使用伊立替康每周×4方案的MTD、2×MTD和3×MTD获得的。
硒对多种化疗药物诱导的毒性具有高度保护作用。此外，硒显著提高了对伊立替康敏感（HCT - 8和FaDu）和耐药（HT - 29和A253）的人肿瘤异种移植瘤的治愈率。当与硒联合使用时，接受伊立替康MTD（100毫克/千克/周×4）治疗的携带HCT - 8和FaDu异种移植瘤的裸鼠实现了高治愈率（100%）。对于HT - 29和A253异种移植瘤，需要给予更高剂量的伊立替康（200和300毫克/千克/周×4）才能实现高治愈率。由于硒对正常组织的选择性保护，才有可能给予这些更高剂量。因此，将硒用作抗癌药物治疗效果的选择性调节剂是新颖的。
我们证明，在携带人结肠癌和头颈鳞状细胞癌异种移植瘤的裸鼠中，硒是抗癌药物治疗效果和选择性的高效调节剂。观察到的体内协同相互作用高度依赖于硒的给药方案。
