Factors influencing intracellular uptake and radiosensitization by 2-nitroimidazoles in vitro
In this study it is shown that the radiosensitization of hypoxic Chinese hamster ovary (HA-1) cells in vitro by misonidazole (MIS) and other 1-substituted 2-nitroimidazoles depends on the rate and extent of intracellular uptake of these radiosensitizers, which in turn is governed by their lipophilicity (expressed as the octanol:water partition coefficient (P)). As the lipophilicity of the compounds decreased, the rate of drug entry into the cells was slower, and below P values of approximately 0.05, peak intracellular drug concentrations were found to be lower than that of MIS (P=0.43). In addition, the number of hydroxyl groups on the side chain of the nitroimidazole molecule influenced the uptake of drug into the cells. For compounds of similar P, but differing in the number of side-chain hydroxyl groups, the addition of a single hydroxyl group to the molecule decreased the amount of drug entering the cell by a factor of approximately 2. These compounds enter the cell by nonmediated passive diffusion since altering the energy (ATP) capacity of the cell by 2-deoxyglucose did not affect uptake. It is also shown that increases in temperature or decreases in pH can increase the intracellular uptake of MIS. For example, equal intracellular and extracellular concentrations (100% uptake) of MIS were obtained if cells were heated to 44-45/sup 0/C for 15 min compared to 20-40% uptake at 37/sup 0/C. Increases in MIS uptake by factors of 2 to 3 could be demonstrated within 30 min when cells were incubated in Hanks' balanced salt solution at pH between 6.0 and 6.3 without loss of cell viability. In addition, MIS uptake in aerobic cultured cells varied from 15 to 60% depending on the cell line and culure conditions used.
- Research Organization:
- Stanford Univ. School of Medicine, CA
- OSTI ID:
- 5896058
- Journal Information:
- Radiat. Res.; (United States), Vol. 93:3
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CHO CELLS
RADIOSENSITIVITY
MISONIDAZOLE
RADIOSENSITIVITY EFFECTS
UPTAKE
CHEMICAL PROPERTIES
MEMBRANE TRANSPORT
RADIOSENSITIZERS
ANIMAL CELLS
ANTINEOPLASTIC DRUGS
AZOLES
DRUGS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
560121* - Radiation Effects on Cells- External Source- (-1987)