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'-amidinohydra zone (CGP 48664A), alpha-difluoromethylornithine (DFMO) and a combinat ion of CGP 48654A-DFMO on tumor growth, cell-cycle phase distribution and polyamine contents. DBA-2, mice were inoculated i.p. with 10(5) L1 210 cells on day 0, treated i.p. on days 1-4 and killed on day 5. As c ompared to controls, CGP 48664A, DFMO and the CGP 48664A-DFMO combinat ion reduced L1210 cell numbers by 33, 43 and 85%, respectively. CGP 48 664A did not affect cell-cycle phase distribution. DFMO and the CGP 48 664A-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 p olyamines, but did not affect spermine. Compared with CGP 48664A, the CGP 48664A-DFMO combination caused lower putrescine and total polyamin es, higher spermine, but no change in spermidine. Compared with DFMO, the CGP 48664A-DFMO combination caused higher putrescine and spermidin e, lower spermine, but no change in total polyamine levels. We conclud e 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 spermidi ne. The data suggest that perturbed polyamine composition rather than reduced spermidine or total polyamine pool size causes a profound grow th inhibition. (C) 1995 Wiley-Liss, Inc.