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Preclinical Antitumor Activity of Temozolomide in Mice: Efficacy against Human Brain Tumor Xenografts and Synergism with 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Developmental Therapeutics Program [J. P., M. R. G.] and Cancer Therapy Evaluation Program [A. D. K., L. V. R., T. D. M.], Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892, and Southern Research Institute, Birmingham, Alabama 35255 [W. R. W.]

Temozolomide, a methylating agent with clinical activity against brain tumors, demonstrated excellent antitumor activity following p.o. administration to athymic mice bearing human brain tumor xenografts. In the early stage s.c. implanted SNB-75 astrocytoma model, a 400-mg/kg dose administered on Day 5 produced 10 of 10 Day 54 tumor-free mice. In later staged s.c. U251 and SF-295 glioblastoma models, a single 600-mg/kg dose produced 9 of 10 Day 86 and 2 of 10 Day 40 tumor-free mice, respectively. In the latter group, a tumor growth delay of >315% was attained. Similar levels of activity were attained with equal total doses on schedules of daily for 5 doses and every fourth day for 3 doses. A single 40-mg/kg i.v. dose of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) also demonstrated excellent activity, producing 9 of 10 tumor-free mice in the SNB-75 model and growth delays of 283 and 301% in the U251 and SF-295 models, respectively. Temozolomide was also highly effective against intracerebral implants of the U251 and SF-295 glioblastomas. Administration of either 600 mg/kg on Day 1 or 200 mg/kg on Days 1, 5, and 9 produced 7 of 9 Day 90 tumor-free mice in the U251 model. In the SF-295 model, a single 400-mg/kg dose or three 200-mg/kg doses produced 3 and 4 of 10 Day 90 tumor-free mice, respectively, and prolonged survival by 127%. A single 40-mg/kg i.v. dose of BCNU was more effective than temozolomide in the intracerebral SF-295 model, and less effective in the intracerebral U251 model. The synergistic potential of temozolomide and BCNU in combination was evaluated in an advanced stage s.c. implanted SF-295 model. When temozolomide was administered 2 h after BCNU on a single treatment day, a dramatic synergistic therapeutic effect was observed in two experiments. For example, single agent doses of temozolomide (600 mg/kg) and BCNU (60 mg/kg) and a combination (400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced growth delays of 190, 258, and >492% (includes 5 of 10 Day 51 tumor-free mice), respectively. Analysis of the data by a quadratic dose response model indicated synergism with significance at P = 0.0001 in both experiments. Synergism also was demonstrated by the isobole method. The reverse sequence was more toxic, but at lower combination doses a synergistic effect was still observed (P = 0.0001). Using the quadratic model, no confirmed modulation of the antitumor activity of temozolomide was demonstrated by i.p. administration of either 10 or 30 mg/kg O⁶-benzylguanine 1 h before or 1 h after temozolomide. These data provide a rationale for the clinical evaluation of temozolomide and BCNU combinations in patients with brain tumors.

¹ These studies were supported in part by Contracts N01-CM-27714 and N01-CM-07315 from the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute.

² To whom requests for reprints should be addressed, at NCI-FCRDC, Fairview Center, Suite 205, 1003 W. 7th Street, Frederick, MD 21701-8527.

Received 4/ 7/94. Accepted 5/12/94.

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