IN-VIVO EFFECTS OF 4-AMIDINOINDAN-1-ONE 2'-AMIDINOHYDRAZONE (CGP 48664A) AND ALPHA-DIFLUOROMETHYLORNITHINE (DFMO) ON L1210 GROWTH, CELL-CYCLE PHASE DISTRIBUTION AND POLYAMINE CONTENTS

We studied the in vivo effects of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A), alpha-difluoromethylornithine (DFMO) and a combination of CGP 48654A-DFMO on tumor growth, cell-cycle phase distribution and polyamine contents. DBA-2, mice were inoculated i.p. with 10(5) L1210 cells on day 0, treated i.p. on days 1-4 and killed on day 5. As compared to controls, CGP 48664A, DFMO and the CGP 48664A-DFMO combination reduced L1210 cell numbers by 33, 43 and 85%, respectively. CGP 48664A did not affect cell-cycle phase distribution. DFMO and the CGP 48664A-DFMO combination caused a moderate and a heavy accumulation in G(0)/G(1)- and G(2)/M-phases, respectively. Compared with controls, the CGP 48664A-DFMO combination reduced putrescine, spermidine and total polyamines, but did not affect spermine. Compared with CGP 48664A, the CGP 48664A-DFMO combination caused lower putrescine and total polyamines, higher spermine, but no change in spermidine. Compared with DFMO, the CGP 48664A-DFMO combination caused higher putrescine and spermidine, lower spermine, but no change in total polyamine levels. We conclude that CGP 48664A potentiates the cystostatic effect of DFMO in vivo. The resulting growth inhibition is accompanied by an accumulation in G(0)/G(1)- and G(2)/M-phases and a reduction of putrescine and spermidine. The data suggest that perturbed polyamine composition rather than reduced spermidine or total polyamine pool size causes a profound growth inhibition. (C) 1995 Wiley-Liss, Inc.