[Biochemical modulation in cancer chemotherapy]

With advances in the understanding of intracellular nucleic acid metabolism, the biochemical modulation of the action of antimetabolites by MTX was discussed as an approach towards the development of more selective chemotherapy. Using high-performance liquid chromatography, the sequential changes occurring in the acid-soluble intra cellular nucleotide pools of L1210 mouse leukemic cells were analysed after treatment with MTX, and a reduction of the dTTP pool to 46% of the control level was observed. Declines in the dCTP, ATR and GTP pools were also reduced to 36%, 30% and 24%, respectively, of the control level after treatment with MTX. Using MTX-5-FU combination chemotherapy, pretreatment with MTX enhanced the intracellular level of FUTP which is one of the active metabolites of 5-FU. There was, however, no significant difference in the value of dTTP levels between MTX-5-FU and 5-FU alone. One of the mechanisms of the synergistic interaction between MTX and 5-FU might therefore be stimulated phosphorylation of 5-FU with an increased PRPP level, which occurs as a result of the MTX-blocked purine de novo pathway. Using MTX-ara C combination chemotherapy, MTX enhanced the intracellular production of ara-CTP, which occurs as a result of MTX reducing the intracellular dCTP pools, following activation of deoxycytidine kinase. More clarification of the effects on intracellular nucleic acid metabolism will aid the development new and increasingly effective drug combinations involving thiopurines. The methods of combination chemotherapy will become more sophisticated as the biochemical modulation effect of the drug is clarified.