ALTERATION OF SENSITIVITY TO CIS-DIAMINE(GLYCOLATE)-PLATINUM(II) (254-S) IN ORAL TUMOR XENOGRAFTS FOLLOWING MULTIPLE APPLICATIONS

The emergence of resistance to platinum analogues is considered to be a major problem in the treatment of head and neck cancer. Therefore, i t is important to clarify the mechanisms of resistance to these analog ues and the mechanisms of the processes related to this resistance. Th e study of emergence of resistance in the solid tumors is particularly relevant. Ln the present study, the effect of a platinum analogue (25 4-S), on the response of an oral carcinoma cell line grown as a xenogr aft in nude mice, was studied. The effect of a full dose administered as a single intraperitoneal injection of 254-S (15 mg/kg X 1) on tumor growth was not significantly different from the effect of repeated in traperitoneal injections of 254-S, administered 3 times at 1/3 of this dose (5 mg/kg x3), or 5 times at 1/5 of this dose (3 mg/kg x5). Howev er, when a single full-dose intraperitoneal injection of 254-S (15 mg/ kg x1) was administered to each group of mice again at the 9th and 12t h weeks after the initial treatment, different effects on tumor growth were observed among each group. The groups which received repeated tr eatment with 254-S (5 mg/kg, x3, or 3 mg/kg x5) showed a decrease in t he inhibition of tumor growth, suggesting the emergence of resistance to 254-S. The study of platinum accumulation in the tumor tissues and a flow cytometric analysis of proliferating cell nuclear antigen (PCNA ) supported the possibility that resistance to 254-S increases in tumo r tissues treated repeatedly. These observations suggest that the pote ntial use of this experimental assay as a model, may provide further i nsights into the therapeutic mechanisms of resistance to antineoplasti c agents in the treatment of solid cancerous head and neck tumors.