ANTITUMOR-ACTIVITY OF PROLONGED AS COMPARED WITH BOLUS ADMINISTRATIONOF 2',2'-DIFLUORODEOXYCYTIDINE IN-VIVO AGAINST MURINE COLON TUMORS

2',2'-Difluorodeoxycytidine (gemcitabine) is a cytidine analogue with established antitumor activity against several experimental tumor type s and against human ovarian and non-small-cell lung cancer. Both precl inical studies and most clinical trials involving patients with solid tumors have focused on short-term administration schedules; however, m echanistic studies indicate that a continuous-infusion schedule may be more effective. We determined the maximal tolerated dose (MTD) of gem citabine in mice using various schedules. At these MTDs we observed co nsiderably better antitumor activity of gemcitabine in two of three mu rine colon carcinoma lines using a prolonged administration as compare d with a standard bolus protocol (i.p. 120 mg/kg q3d x 4). On the latt er schedule, Colon 26-10 grown in BALB/c mice was the most sensitive t umor line, showing a growth-delay factor (GDF, number of doubling time s gained by the treatment) of 6.7, whereas Colon 38 (grown in C57/B16 mice) was the least sensitive tumor, displaying a GDF of 0.9. Prolonge d treatment (q3d x 6) of Colon 26-10 at a lower dose (100 mg/kg) enhan ced the antitumor activity (GDF 9.6) while producing similar toxicity. A similar weight loss was found following the continuous infusion (c. i.) of gemcitabine using Alzet osmotic pumps s.c. for 3 or 7 days (2 m g/kg), but the GDF increased to 2.4 in Colon 38 (C57/B16) as compared with that provided by the bolus injections. Continuous infusion of gem citabine at 15 mg/kg per 24 h q7d x 2 i.v. via the tail vein was more effective than bolus injection against Colon 26-10, with the GDF being > 17.7 and 73% of the tumors regressing completely. However, against Colon 38 tumors this schedule;was not effective (GDF 0.4), even with a 25% higher dose. The plasma pharmacokinetics of gemcitabine was deter mined after one bolus dose (120 mg/kg). The peak concentration of gemc itabine was 225 mu M and that of the deaminated catabolite 2', 2'-difl uorodeoxyuridine (dFdU) was 79 mu M. The elimination of gemcitabine wa s much faster than that of dFdU, with the t(1/2 beta) values being 15 min and 8 h, respectively. For the c.i. schedules, plasma concentratio ns were below the detection limit of the assay (< 0.5 mu M). Our resul ts suggest that prolonged infusion of gemcitabine can give a better an titumor activity than bolus injections and shows promise of being acti ve in clinical trials.