EFFECT OF 1,19-BIS(ETHYLAMINO)-5,10,15-TRIAZANONADECANE ON HUMAN TUMOR XENOGRAFTS

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 M G), 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 betwe en 4 and 12%, which was observed 10-15 days following the initiation o f 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. A t day 73, the growth of the A549 tumor was inhibited by 78 and 89% fol lowing one or two cycles of BE-4-4-4-4, respectively. The mitotic inde x of A549 tumors was 18 times greater in control mice than in those tr eated with BE-4-4-4-4 for one or two cycles 99 days after initiation o f 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 an d 40 mg/kg for BCNU plus BE-4-4-4-4. BCNU alone significantly inhibite d the growth of U-87 MG tumors but not the growth of A519 tumors. Trea tment with the combination of BCNU and BE-4-4-4-4 was significantly be tter 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 combin ation, there was a significant weight loss, which was not observed for animals treated with either agent atone. These data suggest a role fo r BE-4-4-4-4 in the treatment of brain, lung, and colon tumors.