Abstract
Changes in glutathione levels were determined in tissues of 11- to 12-week-old Swiss albino mice at different stages of Dalton's lymphoma tumor growth and following cisplatin (8 mg/kg body weight, ip) treatment for 24-96 h, keeping 4-5 animals in each experimental group. Glutathione levels increased in spleen of tumor-bearing compared to normal mice (9.95 +/- 0.14 vs 7.86 +/- 1.64 micromol/g wet weight, P<or=0.05) but decreased in blood (0.64 +/- 0.10 vs 0.85 +/- 0.09 mg/ml) and testes (9.28 +/- 0.15 vs 10.16 +/- 0.28 micromol/g wet weight, P<or=0.05). Dalton's lymphoma cells showed an increase in glutathione concentration (4.43 +/- 0.26 micromol/g wet weight) as compared to splenocytes, their normal counterpart (3.62 +/- 0.41 micromol/g wet weight). With the progression of tumor in mice, glutathione levels decreased significantly in testes (approximately 10%) and bone marrow cells (approximately 13%) while they increased in Dalton's lymphoma cells (28-46%) and spleen (15-27%). Glutathione levels in kidney, Dalton's lymphoma cells and bone marrow cells (8.50 +/- 1.22, 4.43 +/- 0.26 and 3.28 +/- 0.17 micromol/g wet weight, respectively) decreased significantly (6.04 +/- 0.42, 3.51 +/- 0.32 and 2.17 +/- 0.14 micro mol/g wet weight, P<or=0.05) after in vivo cisplatin treatment for 24 h. Along with a decrease in glutathione level, the glutathione-S-transferase (GST) activity also decreased by 60% in tumor cells after cisplatin treatment. The elevated drug uptake by the tumor cells under the conditions of reduced glutathione concentration and GST activity after treatment could be an important contributory factor to cisplatin's anticancer activity leading to tumor regression. Furthermore, lower doses of cisplatin in combination with buthionine sulfoximine (an inhibitor of glutathione synthesis) may be useful in cancer chemotherapy with decreased toxicity in the host.
Highlights
Cis-diamminedichloroplatinum (II), commonly known as cisplatin, is a widely used anticancer drug against several animal [1,2] and human malignancies [3]
Along with a decrease in glutathione level, the glutathione-S-transferase (GST) activity decreased by 60% in tumor cells after cisplatin treatment
Platinum uptake and glutathione-S-transferase (GST; EC 2.5.1.18) activity were measured in Daltons lymphoma cells collected from mice under different experimental conditions in an attempt to identify the mechanism of GSH changes and its significance in cisplatin-mediated cancer chemotherapy
Summary
Cis-diamminedichloroplatinum (II), commonly known as cisplatin, is a widely used anticancer drug against several animal [1,2] and human malignancies [3]. In addition to reacting with DNA, cisplatin affects the host immune response [5], cell surface [6], tissue calcium and potassium concentrations [7], various enzymes such as 5'-nucleotidase, arginase, cathepsins and lactate dehydrogenase [8], and mitochondria [9], properties that have led to the proposal of the involvement of cisplatin in multistep and multilevel actions on the tumor cell/host relationship during cisplatin-mediated chemotherapy [8,9]. In vitro studies have demonstrated that cancer cells resistant to alkylating agents including cisplatin can be made sensitive to these drugs through BSO-induced glutathione depletion [17]. Platinum uptake and glutathione-S-transferase (GST; EC 2.5.1.18) activity were measured in Daltons lymphoma cells collected from mice under different experimental conditions in an attempt to identify the mechanism of GSH changes and its significance in cisplatin-mediated cancer chemotherapy
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