POTENTIATION OF CISPLATIN ANTITUMOR-ACTIVITY USING A VITAMIN-D ANALOGIN A MURINE SQUAMOUS-CELL CARCINOMA MODEL SYSTEM

In a murine squamous cell carcinoma (SCC) model, we have demonstrated that both 1,25-dihydroxycholecalciferol (1,25-D-3) and the analogue 1, 25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553) have significan t in vitro and in vivo antitumor activity. We have examined here the c ell cycle effect of 1,25-D, and Ro23-7553 on SCCVII/SF tumor cells by quantitating nuclear DNA using a detergent-trypsin method via flow cyt ometry analysis. Both 1,25-D, and Ro23-7553 resulted in a significant increase of cells in G(0)-G(1), with an accompanying decrease of cells in S phase. The ability to arrest cells in G(0)-G(1) has been exploit ed by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diam minodichloroplatinum; cDDP). Using the in vitro clonogenic assay, pret reatment with Ro23-7553 for 24-48 h significantly enhanced cDDP-mediat ed 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 treat ment, cDDP (1-6 mg/kg) was administered. Using the in vivo excision tu mor cell clonogenic assay, in which tumors were removed from animals 2 4 h after cDDP treatment and plated in a clonogenic assay, pretreatmen t 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 incre ase in tumor regrowth delay was observed when animals were pretreated before cDDP with Ro23-7553 as compared to either agent alone. These re sults demonstrate a significant enhanced antitumor effect with Ro23-75 53 pretreatment before cDDP both in vitro and in vivo and suggest that Ro23-7553 mag potentiate cDDP cytotoxicity through effects on cell cy cle progression.