Cancer research
-
Derivatives of N-hydroxy-N'-aminoguanidine were recently shown to be efficient inhibitors of mammalian ribonucleotide reductase and cancer cell growth. We investigated the effects of the 1-isoquinolylmethylene and the 2-quinolylmethylene derivatives of N-hydroxy-N'-aminoguanidine on intracellular targets, cell viability, and cell cycle of L1210 mouse leukemia cells. A 2-h exposure of L1210 cells to either drug in the low micromolar concentration range led to inhibition of intracellular ribonucleotide reductase activity and DNA synthesis. ⋯ As shown by flow cytometry, the N-hydroxy-N'-aminoguanidine isoquinoline derivative at 0.5-10 microM led to an elevation of G0/G1 cells and a decrease of G2/M and S cells. At 10 microM of the drug this shift remained unchanged over 48 h. L1210 cells treated with 0.5, 1, and 2 microM of the drug overcame the block after 4 to 12 h of exposure and progressed through S- and G2/M-phase in a synchronized manner.
-
The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity. When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo GM1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated. ⋯ Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo GM1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activated killer cells.(ABSTRACT TRUNCATED AT 400 WORDS)