Low pH does not affect the dose response for 5'-amino-5'-deoxythymidine modulation of IdUrd DNA incorporation and radiosensitization in a human bladder cancer cell line.
We report that coincubation of 647V cells for one cell cycle with low concentrations (30 microM) of 5'-amino-5'-deoxythymidine increased IdUrd DNA incorporation and radiosensitivity at low extracellular pH (pHe 6.8) in a fashion similar to treatment at normal pHe. IdUrd DNA incorporation is inhibited by high (300 microM) 5'-AdThd concentrations at both normal and low pHe (7.4 and 6.8), resulting in no significant radiosensitization. These results at low pHe were not anticipated based on previously published studies of 5'-AdThd modulation of thymidine kinase (TK) activity and nucleoside cellular uptake. Our results suggest that regulation of intracellular pH (pHi) during the course of one cell cycle negates the 5'-AdThd dose-dependent modulation of TK activity demonstrated previously. Flow cytometric measurement of pHi in 647V cells showed that normal pHi (pH 7.4) was maintained in 647V cells over a 12- to 24-h exposure to low pHe (pH 6.8). Thus the concomitant use of IdUrd and high concentrations of 5'-AdThd (> 30 microM) is unlikely to result in selective in vivo radiosensitization of human tumors under conditions which are intermittently or chronically acidic. However, low concentrations of 5'-AdThd may prove to be an effective in vivo modulator of IdUrd radiosensitization of human tumors under both normal and acidic conditions.
Kunugi
K A
KA
Department of Human Oncology, University of Wisconsin, Madison 53792.
Miller
E M
EM
Vazquez-Padua
M A
MA
Kinsella
T J
TJ
D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis* / Q000187:drug effects / Q000528:radiation effects*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007065:Idoxuridine / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D001749:Urinary Bladder Neoplasms
D004273:DNA, Neoplasm; D015224:Dideoxynucleosides; D011838:Radiation-Sensitizing Agents; C024082:5'-amino-5'-deoxythymidine; D007065:Idoxuridine