ACTIVITY OF (-)-2'-DEOXY-3'-OXACYTIDINE (BCH-4556) AGAINST HUMAN TUMOR COLONY-FORMING-UNITS

Background: BCH-4556 ((-)-2'-deoxy-3'-oxacytidine) is an L-nucleoside analogue shown to have broad preclinical anti-cancer activity, particu larly against solid neoplasms such as prostate, renal, and hepatoma in vitro and in vivo, in contrast to cytosine arabinoside (ara-C) which is preferentially active against leukemia. Materials and methods: The antitumor activity of BCH-4556 was evaluated using human tumor colony- forming unit (HTCFU) assay, in which fresh tumor specimens were taken directly from patients with and without prior chemotherapy. Results: O verall, in vitro responses (50% or less survival compared to untreated controls) were observed in 11% (two of 18), 29% (five of 17) and 50% (nine of 18) of specimens treated for one hour with BCH-4556 at 1, 10 and 100 mu g/ml, respectively; and 16% (nine of 55), 32% (24 of 74), 4 8% (35 of 73) and 65% (11 of 17) of specimens treated continuously wit h BCH-4556 at 0.1, 1, 10 and 100 mu g/ml, respectively. With the one-h our schedule, a significant difference in response rates was noted bet ween 100 mu g/ml and 1 mu g/ml (P = 0.02). With the continuous schedul e, significant differences in response rates were observed between 1 m u g/ml and 0.1 mu g/ml (P = 0.02), between 10 mu g/ml and 0.1 mu g/ml (P = 0.0001) as well as between 10 mu g/ml and 1 mu g/ml (P = 0.01). A trend suggesting the superiority of continuous exposure was observed in paired specimens (n = 18) at comparable drug concentrations. Activi ty was noted against ovarian (nine of 16 = 56%), renal (three of four = 75%), and melanoma (two of two = 100%) HTCFU at 10 mu g/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 mu g/ml using the continuous exposure. Twe nty-three specimens showed similar responses with both drugs; seven sh owed better responses with BCH-4556; and two showed better responses w ith paclitaxel (P = 0.18). Conclusions: Promising activity was observe d with BCH-4556 against ovarian, renal, and melanoma HTCFU. There appe ared to be a positive relationship between BCH-4556 concentration and response using both one-hour and continuous exposures. Continuous expo sure to BCH-4556 provided high response rates especially at concentrat ions above 10 mu g/ml. For both one-hour and continuous exposures, BCH -4556 had similar, and at times, greater potency than paclitaxel again st the same tumor specimens in the present study.