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 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.
Dolan
M E
ME
Division of Hematology/Oncology, University of Chicago Medical Center, Illinois 60637.
Fleig
M J
MJ
Feuerstein
B G
BG
Basu
H S
HS
Luk
G D
GD
Casero
R A
RA
Marton
L J
LJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy; D002330:Carmustine / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C082768:BE 4-4-4-4; D013096:Spermine; D002330:Carmustine