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.