By F. M. Huennekens, Y. D. Montejano, K. S. Vitols (auth.), Youcef Rustum, John J. McGuire (eds.)
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Extra info for The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy
That is interesting since nobody knows what its role is. Dr. Rustum: I noticed in your uptake experiment with the R versus S, the highest R-isomer concentration was around 10 ~ M. Yet for the inhibition assays you went to a much higher concentration. As you know, the plasma concentration in patients is on the order of 80100 ~ M. Have you looked at the transport of R-isomer at a concentra tion around 100 ~ M or so? 23 Dr. Jolivet: No we haven't, because of the expense. practically, we've only been able to generate concentrations up to 10 ~M in tissue culture experiments.
Dr. Schilsky: I just wanted to make a couple of comments. We've looked at the cellular pharmacology of the isomers in human colon cancer cells, HT29 cells, and we are at about the same level of accomplishment as you are with the CEM cells. The data look very similar. We found that the transport of the 6R isomer is about 30-fold less than the 6S isomer' in colon cancer cells. The 6R isomer does support the growth of folate depleted colon cancer cells but it's about 400-fold less potent in dOing so.
Dr. Duch: Yes, that surprised us also. One thing that we did find was that there wasn't a lot of conversion of 5-formyl in the mouse; we didn't see large increases in plasma levels of 5-methyl and that bothered us. However, there was a study awhile back that also showed that you con't get a lot of 5-methyl formed in mice. It may be a function of the dose that we are giving; that we are saturating the conversion system for one thing. We are going to do a dose response and see what we get at different doses to see whether that holds up or whether the percentage of 5-methyl increases.
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