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Effect of 1,19-Bis(ethylamino)-5,10,15-triazanonadecane on Human Tumor Xenografts¹

Division of Hematology/Oncology, The University of Chicago Medical Center, Chicago, Illinois 60637 [M. E. D., M. J. F.]; Brain Tumor Research Center of the Department of Neurological Surgery [H. S. B., B. G. F.], Department of Laboratory Medicine [B. G. F.], and Department of Pediatrics [B. G. F.], School of Medicine, University of California, San Francisco, California 94143; Gastroenterology Research, Department of Veterans Affairs Medical Center, and The University of Texas Southwestern Medical Center, Dallas, Texas 75216 [G. D. L.]; Johns Hopkins Oncology Center Laboratories, Johns Hopkins School of Medicine, Baltimore, Maryland 21231 [R. A. C.]; and Departments of Pathology and Laboratory Medicine, Oncology, and Human Oncology, University of Wisconsin-Madison Medical School, Madison, Wisconsin 53706 [L. J. M.]

The polyamine analogue 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4), 5 mg/kg i.p., was given twice daily on days 0–3 and 7–10 (cycle 1) to nude mice with human malignant gliomas (SF-767 and U-87 MG), lung adenocarcinoma (A549), and colon carcinomas (HCT116 and HT29). A second cycle of drug was given to mice with SF-767 and A549 tumors on days 42–45 and 49–52. The maximum animal weight loss varied between 4 and 12%, which was observed 10–15 days following the initiation of treatment, but no overt toxic reactions were noted. The SF-767 brain tumors were extremely responsive to BE-4-4-4-4 alone (3 of 8 complete regressions after 2 cycles); however, the growth of the U-87 MG brain tumor was only slightly inhibited by BE-4-4-4-4 treatment. There was significant inhibition of tumor growth after treatment with one cycle of BE-4-4-4-4 in animals carrying the A549, HCT116, and HT29 tumors. At day 73, the growth of the A549 tumor was inhibited by 78 and 89% following one or two cycles of BE-4-4-4-4, respectively. The mitotic index of A549 tumors was 18 times greater in control mice than in those treated with BE-4-4-4-4 for one or two cycles 99 days after initiation of treatment. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was given to mice carrying the U-87 MG or A549 tumors on day 4 (cycle 1) and day 46 (cycle 2) in the maximal tolerated dose of 50 mg/kg for BCNU alone and 40 mg/kg for BCNU plus BE-4-4-4-4. BCNU alone significantly inhibited the growth of U-87 MG tumors but not the growth of A549 tumors. Treatment with the combination of BCNU and BE-4-4-4-4 was significantly better than BCNU alone for A549 tumors and better than BE-4-4-4-4 alone for U87 tumors. However, in both animal groups treated with the combination, there was a significant weight loss, which was not observed for animals treated with either agent alone. These data suggest a role for BE-4-4-4-4 in the treatment of brain, lung, and colon tumors.

¹ This work was supported in part by Grants CA 47228 (to M. E. D.), CA 49409 (to H. S. B.), CA 13525 (to H. S. B., B. G. F., and L. J. M.), CA 15206 (to G. D. L.), and CA 58184, and CA 51085 (to R. A. C.) from the National Cancer Institute, the Patterson Chair, and the National Brain Tumor Foundation.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, 5841 S. Maryland Ave., Box MC2115, The University of Chicago Medical Center, Chicago, IL 60637.

Received 2/14/94. Accepted 7/ 6/94.

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