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Uptake of WR-2721 Derivatives by Cells in Culture: Identification of the Transported Form of the Drug¹

Departments of Radiology [P. M. C-J., J. A. A., J. F. W.] and Chemistry [G. D. S., R. C. F.], University of California, San Diego, La Jolla, California 92093

When V79-171 cells are incubated in medium to which WR-1065 has been added the cells accumulate WR-1065 and disulfides of WR-1065 (WRSS) in a ratio of about 10:1. Analysis of the culture medium showed that it contained primarily WR-1065 but that significant levels of the symmetrical disulfide WR-33278 and of the mixed disulfide of WR-1065 with cysteine were also present. Since incubation of cells with either of the latter disulfides did not lead to uptake it was concluded that WR-1065 is the form of the drug taken up. The uptake rate on a per cell basis was shown to be independent of cell density, to be first order in the WR-1065 concentration in the incubation medium, to increase as [H⁺]^-1.2 at medium pH values from pH 6.8 to 8.0, and to have a Q₁₀ value (rate increase per 10°C temperature increase) of 2.9 ± 0.3 between 2 and 37°C. Rates of WR-1065 uptake measured for HeLa, HT29/SP-1d, Me-180-VCII, Ovary 2008, and WI-38 cell lines were found to be similar to that measured for V79-171 cells. The results are consistent with uptake by nonmediated, passive diffusion of the uncharged form of WR-1065 across the plasma membrane but uptake mediated by a membrane transport system could not be rigorously excluded. Based upon these results and earlier findings it is postulated that the lower drug uptake seen in tumors as compared with normal tissues in animals treated with WR-2721 results from a combination of (a) slower conversion of WR-2721 to WR-1065 in tumors as a consequence of the lower inherent level of alkaline phosphatase and lower pH in tumors and (b) a decreased uptake rate of the WR-1065 present in tumors as a consequence of their lower pH.

¹ This work was supported by Grant CA-39582 from the National Cancer Institute.

² National Institutes of Health predoctoral trainee under Grant GM-07313.

³ To whom requests for reprints should be addressed, at Department of Chemistry, D-006, University of California, San Diego, La Jolla, CA 92093.

Received 10/ 7/87. Revised 3/ 7/88. Accepted 3/15/88.

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