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Synergistic antileukemic effect of two polyamine synthesis inhibitors. Host survival and cell-cycle kinetic analysis
Abstract:
alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia. Used as a single agent (administered p.o. as a 3% solution in tap water), DFMO exerted a weak therapeutic effect against this tumor. The therapeutic effect of MGBG (administered i.p. at 50 mg/kg/day) was only slightly better. However, 1-3 days of pretreatment with DFMO strongly potentiated the effect of MGBG treatment. Thus, mice treated with the combination exhibited an increase in life span of up to 138%. The prolonged survival of leukemic mice treated with a combination of DFMO and MGBG was associated with inhibition of polyamine synthesis and a marked decrease in the spermidine and spermine content of the tumor cells as compared to untreated controls. As a consequence, there was a continuous decrease in the S- and G2-phase fractions with a concomitant increase in G1. Used singly, DFMO and MGBG had no significant effect on the cell-cycle distribution. The effects of the combination of DFMO and MGBG on the cell-cycle distribution are consistent with the contention that polyamine deficiency primarily interferes with initiation of DNA synthesis. However, the possibility that selective S-phase kill partly contributes to this change in cell-cycle distribution cannot be excluded.
Insights
alpha-Difluoromethylornithine (DFMO) combined with methylglyoxal-bis(guanylhydrazone) (MGBG) significantly increased lifespan in leukemia-bearing mice. This combination therapy inhibited polyamine synthesis, impacting tumor cell cycle progression.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Systemic L1210 leukemia is a challenging cancer model.
- Ornithine decarboxylase (ODC) is a key enzyme in polyamine synthesis.
- Polyamines are crucial for cell growth and proliferation.
Purpose of the Study:
- To evaluate the therapeutic efficacy of alpha-Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanylhydrazone) (MGBG) in treating L1210 leukemia.
- To investigate the synergistic effects of combining DFMO and MGBG.
- To understand the impact of this combination therapy on polyamine metabolism and cell cycle progression.
Main Methods:
- Mice with systemic L1210 leukemia were treated with DFMO alone, MGBG alone, or a combination of both agents.
- DFMO was administered orally, and MGBG was administered intraperitoneally.
- Tumor cell polyamine content and cell cycle distribution were analyzed.
Main Results:
- Single-agent treatment with DFMO or MGBG showed limited therapeutic effects.
- Pretreatment with DFMO significantly potentiated the therapeutic effect of MGBG, increasing lifespan by up to 138%.
- Combination therapy led to inhibition of polyamine synthesis, decreased spermidine and spermine levels in tumor cells, and altered cell cycle distribution (decreased S and G2 phases, increased G1 phase).
Conclusions:
- The combination of DFMO and MGBG demonstrates significant synergistic anti-leukemic activity.
- Polyamine depletion induced by combination therapy is associated with altered tumor cell cycle kinetics.
- The findings suggest that polyamine deficiency primarily affects DNA synthesis initiation, potentially offering a novel therapeutic strategy for leukemia.