Cancer research
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Certain N-alkylated analogues of the natural polyamine spermine, such as N1,N11-diethylnorspermine (DENSPM), rapidly deplete intracellular polyamine pools by down-regulating the biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, and by potently up-regulating the polyamine catabolizing enzyme, spermidine/spermine N1-acetyltransferase. On the basis of previously reported antitumor activity in human tumor xenograft model systems, DENSPM is currently undergoing Phase I clinical trials against human melanoma and other solid tumors. The antiproliferative activity of this analogue against the multidrug resistance (MDR) phenotype was examined in three MDR sublines of human melanoma RPMI-7932 cells, which were shown to be 2-to 10-fold resistant to classical MDR agents. ⋯ Collateral sensitivity of the MDR sublines to DENSPM is partially attributable to the finding that analogue (and spermidine) uptake in the sublines was about 2-fold higher (after 2 h) than in the parent cells. The presence of disturbances in polyamine homeostasis and increased sensitivity to DENSPM in three independently selected cell line variants suggests that they may be generally associated with the MDR phenotype in human melanoma and possibly other tumor cells. The collateral sensitivity of human melanoma MDR variants to DENSPM represents a possible therapeutic indication which should be considered during the ongoing clinical evaluation of this drug.
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We investigated the effects of somatostatin analogues and a synthetic bombesin/gastrin-releasing peptide (GRP) antagonist on the growth of the human malignant glioma cell lines U-87MG and U-373MG transplanted to nude mice or cultured in vitro. Nude mice bearing s.c. implanted U-87MG or U-373MG tumors were treated for 4 and 6 weeks, respectively, with various somatostatin analogues or bombesin/GRP antagonist RC-3095. Somatostatin analogues RC-160, RC-160-II, and RC-101-I, given s.c. in doses of 100 micrograms/animal/day, inhibited the growth of U-87MG xenografts as shown by more than 60% reduction in tumor volumes and 45% reduction in tumor weights compared with the control group. ⋯ In studies in vitro, RC-3095, added to the culture medium, significantly inhibited the proliferation of U-87MG and U-373MG cells in the presence of GRP(14-27), as measured by cell number, but only a moderate suppression of growth of both cell lines was observed with somatostatin analogue RC-160. These results demonstrate that bombesin/GRP antagonist RC-3095 and somatostatin analogues such as RC-160 can inhibit the growth of human glioblastoma cell lines U-87MG and U-373MG in vitro as well as in vivo. Our work suggests the merit of further investigations of these analogues for the possible development of new approaches for treatments of patients with malignant gliomas.