Activity of (-)-2'-deoxy-3'-oxacytidine (BCH-4556) against human tumor colony-forming units |
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Authors: | L. L. Siu G. Attardo E. Izbicka R. Lawrence C. Cerna L. Gomez K. Davidson C. Finkle C. Marsolais E. K. Rowinsky D. D. Von Hoff |
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Affiliation: | (1) Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, TX, USA;(2) BioChem Therapeutic Inc., Laval, Quebec, Canada |
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Abstract: | Background: BCH-4556 ((-)-2-deoxy-3-oxacytidine) is an L-nucleoside analogue shown to have broad preclinical anticancer activity, particularly 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: Overall, 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 µg/ml, respectively; and 16% (nine of 55), 32% (24 of 74), 48% (35 of 73) and 65% (11 of 17) of specimens treated continuously with BCH-4556 at 0.1, 1, 10 and 100 µg/ml, respectively. With the one-hour schedule, a significant difference in response rates was noted between 100 µg/ml and 1 µg/ml (P = 0.02). With the continuous schedule, significant differences in response rates were observed between 1 µg/ml and 0.1 µg/ml (P = 0.02), between 10 µg/ml and 0.1 µg/ml (P = 0.0001), as well as between 10 µg/ml and 1 µg/ml (P = 0.01). A trend suggesting the superiority of continuous exposure was observed in paired specimens (n = 18) at comparable drug concentrations. Activity was noted against ovarian (nine of 16 = 56%), renal (three of four = 75%), and melanoma (two of two = 100%) HTCFU at 10 µg/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 µg/ml using the continuous exposure. Twenty-three specimens showed similar responses with both drugs; seven showed better responses with BCH-4556; and two showed better responses with paclitaxel (P = 0.18).Conclusions: Promising activity was observed with BCH-4556 against ovarian, renal, and melanoma HTCFU. There appeared to be a positive relationship between BCH-4556 concentration and response using both one-hour and continuous exposures. Continuous exposure to BCH-4556 provided high response rates especially at concentrations above 10 µg/ml. For both one-hour and continuous exposures, BCH-4556 had similar, and at times, greater potency than paclitaxel against the same tumor specimens in the present study. |
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Keywords: | BCH-4556 cloning assay L-nucleoside analogue |
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