Effect of L-buthionine sulfoximine on the radiation response of human renal carcinoma cell lines.
BACKGROUND
Renal cell carcinoma (RCC) is a progressive and relatively radioresistant disease. Currently, no data are available on the in vitro radiobiologic characterization of renal tumor cells to the authors' knowledge.


METHODS
Two RCC were cultured from specimens from previously untreated patients after either surgical resection of the primary tumor or from the malignant ascites. These two cell lines were characterized with respect to cytogenetic abnormalities, gamma radiation survival response, intracellular levels of glutathione and its related detoxification enzymes, and the effect of glutathione depletion on radiation toxicity.


RESULTS
The two RCC grew as adherent monolayer cultures with a median doubling time of 29 hours and 37 hours, respectively. Histopathologic analysis of the tumor cells grown in the renal capsule of the athymic mice confirmed their epithelial neoplastic growth. Both cell lines were aneuploid (range, 65-100 chromosomes) and had several marker chromosomes, including those derived from chromosomes 3, 7, and 11. In vitro radiation survival analysis indicated the relative radioresistance (RR; Do, 2.35 Gy) and relative radiosensitivity (RS; Do, 1.42 Gy), respectively, of these tumor cell lines. The levels of intracellular glutathione (GSH) were higher in the RR cells compared with the RS cells. The enzymatic activities of GSH S-transferase, GSH reductase, and the levels of GSH peroxidase and superoxide dismutase were elevated in the RS cells compared with the RR cells. L-Buthionine sulfoximine (BSO) treatment (concentration, 20 microM, applied for 17 hours) resulted in 77% and 63% GSH depletion compared with the untreated RR and RS cells, respectively. Pretreatment with higher concentration of BSO (50 microM for 17 hours) caused a modest radiosensitization of the RR cells (Do, 1.78 Gy).


CONCLUSIONS
RCC have a differential pattern of radiosensitivity. BSO treatment causes moderate radiosensitization of the relatively radioresistant renal tumor cells.
Leung
S W
SW
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC 20007.
Mitchell
J B
JB
al-Nabulsi
I
I
Friedman
N
N
Newsome
J
J
Belldegrun
A
A
Kasid
U
U
D000818:Animals; D019328:Buthionine Sulfoximine; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011838:Radiation-Sensitizing Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione