Abstract
The effects of methotrexate (MTX) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (BW50197) on the colony forming ability of L5178Y cells were compared. Two sub-lines of cells were used, one sensitive to methotrexate and the other resistant. In addition, the inhibitory effects of BW50197 against dihydrofolate reductase (DHFR) extracted from the MTX resistant cells were compared with those of MTX and pyrimethamine. It was found that although BW50197 was a less effective inhibitor of DHFR than MTX, it was superior to MTX at high concentrations in killing MTX resistant cells, and this superiority increased with the time of exposure to the drugs. These findings suggest that (a) when antifolate compounds are screened for antitumour activity it is insufficient simply to assess them on the basis of their ability to inhibit DHFR and (b) BW50197 should be given clinically so as to achieve the highest possible tissue concentration for the longest possible time consistent with the safety of the patient.
Highlights
Summary.-The effects of methotrexate (MTX) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (BW50197) on the colony forming ability of L5178Y cells were compared
Our interest in activity against transplantable mouse BW50197 was stimulated by the observatumours, Clarke et al (1952) showed that tion by Nichol (1968) that inhibition of a one of this class of agents, 2,4-diamino-5- methotrexate resistant tumour (the (3',4'-dichlorophenyl)-6-methylpyrimidine Walker carcinoma 256) could be achieved (BW50197) was effective in by this drug which showed a more inhibiting the growth of the sarcoma 180. favourable therapeutic index against this Further studies showed that this com- tumour than pyrimethamine (Mishra, pound was effective in controlling Rosen and Nichol, 1967; Sotobayashi, leukaemia (Burchenal et al, 1952) and the Rosen and Nichol, 1966)
A comparison of the effects of BWr50197 on crude extracts of dihydrofolate reductase from RL50197 cells with that of known antifolates such as MTX and pyrimethamine yielded the results shown in the following table: BW50197 is a less
Summary
Summary.-The effects of methotrexate (MTX) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (BW50197) on the colony forming ability of L5178Y cells were compared. It was found that BW50197 was a less effective inhibitor of DHFR than MTX, it was superior to MTX at high concentrations in killing MTX resistant cells, and this superiority increased with the time of exposure to the drugs. These findings suggest that (a) when antifolate compounds are screened for antitumour activity it is insufficient to assess them on the basis of their ability to inhibit DHFR and (b) BW50197 should be given clinically so as to achieve the highest possible tissue concentration for the longest possible time consistent with the safety of the patient. GOLDIE effects of BW50197 and methotrexate (MTX) on MTX-sensitive and MTXresistant lines of L5178Y lymphoblasts in culture
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