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Potentiation of Cisplatin Antitumor Activity Using a Vitamin D Analogue in a Murine Squamous Cell Carcinoma Model System¹

Departments of Otolaryngology [B. W. L., W-D. Y., M. C. M., D. M. R., C. S. J.], Medicine [D. L. T.], and Pharmacology [C. S. J.], University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

In a murine squamous cell carcinoma (SCC) model, we have demonstrated that both 1,25-dihydroxycholecalciferol (1,25-D₃) and the analogue 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553) have significant in vitro and in vivo antitumor activity. We have examined here the cell cycle effect of 1,25-D₃ and Ro23-7553 on SCCVII/SF tumor cells by quantitating nuclear DNA using a detergent-trypsin method via flow cytometry analysis. Both 1,25-D₃ and Ro23-7553 resulted in a significant increase of cells in G₀-G₁, with an accompanying decrease of cells in S phase. The ability to arrest cells in G₀-G₁ has been exploited by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diamminodichloroplatinum; cDDP). Using the in vitro clonogenic assay, pretreatment with Ro23-7553 for 24–48 h significantly enhanced cDDP-mediated tumor cell kill as compared to concurrent treatment with Ro23-7553 and cDDP or cDDP alone. To examine the effect of Ro23-7553 and cDDP in vivo, C3H/HeJ mice with 9–14-day SCC tumors were treated either for 3 days with varying i.p. doses of Ro23-7553 or for 7 days continuously through the use of Alzet pumps, and on the last day of Ro23-7553 treatment, cDDP (1–6 mg/kg) was administered. Using the in vivo excision tumor cell clonogenic assay, in which tumors were removed from animals 24 h after cDDP treatment and plated in a clonogenic assay, pretreatment with Ro23-7553 markedly enhanced cDDP-mediated clonogenic tumor cell kill, even at low doses of cDDP as compared to cDDP treatment alone. Similarly, a significant decrease in fractional tumor volume and increase in tumor regrowth delay was observed when animals were pretreated before cDDP with Ro23-7553 as compared to either agent alone. These results demonstrate a significant enhanced antitumor effect with Ro23-7553 pretreatment before cDDP both in vitro and in vivo and suggest that Ro23-7553 may potentiate cDDP cytotoxicity through effects on cell cycle progression.

¹ This work was supported by USPHS Grants CA67267 and CA60397 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at Department of Otolaryngology, University of Pittsburgh School of Medicine, 203 Lothrop Street, Room 110, Pittsburgh, PA 15213-2582. Phone: (412) 647-6224; Fax: (412) 647-8720; E-mail: candacej@vms.cis.pitt.edu.

Received 4/18/97. Accepted 7/ 7/97.

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