Radiosensitizer-DNA interactions in relation to intracellular uptake.
We have studied the intracellular uptake of a number of neutral, acidic, and basic radiosensitizers. For neutral sensitizers, we observed a correlation between the measured intracellular concentration and sensitization, but for bases, a large change in average intracellular concentration results in only a small change in sensitization. In addition, by modifying the intralysosomal pH, we have altered the measured average intracellular concentration of the weak base pimonidazole by a factor of two, although this had no detectable effect upon sensitization. Using spin filtration of solutions of sensitizers with naked calf thymus DNA or chromatin we have assessed the affinity of DNA for sensitizers with different prototropic and lipophilic properties. We have also shown that this anomalous behavior of the basic sensitizers could be partly explained on the basis of intracellular localization adjacent to the DNA due to ionic interactions. Thus, intracellular localization needs to be considered when interpreting average intracellular uptake data.
Stratford
M R
MR
Gray Laboratory of the Cancer Research Campaign, Mount Vernon Hospital, Northwood, Middlesex, England.
Dennis
M F
MF
Watts
M E
ME
Watfa
R R
RR
Woodcock
M
M
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*
D011838:Radiation-Sensitizing Agents; D004247:DNA