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21 Role of calcium in the modulation of gastrin secretion due to cisplatin treatment

Cisplatin, an anticancer drug, is associated with severe nephrotoxicity and gastrointestinal toxicities. In rats it induces bloating of the stomach in absence of emesis. Calcium supplements have been shown to prevent stomach bloating in rats and protect various enzymatic functions. Gastrin is one of the main polypeptides secreted from the stomach and has been shown to be suppressed after the cisplatin treatment. The present study was undertaken to test if calcium supplements could compromise the inhibition of gastrin production after the cisplatin treatment both in vitro and in vivo, using in situ hybridization, Northern blot and immunocytochemical methods. For the in vitro study, gastrin secreting RIN B6 cell line was cultured in the D-MEM with 10% fetal bovine serum under 5% CO2. Calcium chloride (1.8 and 3.6 mM) was used to raise the level of calcium in the culture medium. Cisplatin (10 mg/ml) was added to the experimental group 12 hours after the calcium supplement. After another 12 hours of the cisplatin treatment, the cells were treated with guanidine isothiocyanate for RNA extraction. For the in vivo study, male Wistar rats were treated with cisplatin (9 mg/kg). Another group of animals pretreated with vitamin D (3 mg/kg/week)was given the same dose of cisplatin (9 mg/kg). The rats were sacrificed at 1, 6, 10 and 15 days after cisplatin treatment. The stomach tissues were homogenized in guanidine isothiocyanate, and RNA was extracted from the stomach tissues. Northern blot tests were performed with oligonucleotide probe tailed with Digoxin labeled UTP. The results demonstrated that gastrin mRNA level was much lower in the cisplatin treated RIN B6 cells, but in the calcium pretreated cells, gastrin mRNA level was higher compared to cisplatin treated cells. Gastrin mRNA level from the rats which only received cisplatin treatment demonstrated a decrease at day 1 through day 6. However, The levels increased at day 10 and reached a normal at day 15. In the vitamin D pretreated rats, the gastrin mRNA levels were close to normal even at day 1 and day 6 after cisplatin treatment. In conclusion, calcium supplement can minimize the inhibition of gastrin mRNA transcription due to the cisplatin treatment.

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