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, 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.


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 micrograms/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 micrograms/ml, respectively. With the one-hour schedule, a significant difference in response rates was noted between 100 micrograms/ml and 1 microgram/ml (P = 0.02). With the continuous schedule, significant differences in response rates were observed between 1 microgram/ml and 0.1 microgram/ml (P = 0.02), between 10 micrograms/ml and 0.1 microgram/ml (P = 0.0001), as well as between 10 micrograms/ml and 1 microgram/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 micrograms/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 micrograms/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 micrograms/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.
Siu
L L
LL
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
Attardo
G
G
Izbicka
E
E
Lawrence
R
R
Cerna
C
C
Gomez
L
L
Davidson
K
K
Finkle
C
C
Marsolais
C
C
Rowinsky
E K
EK
Von Hoff
D D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology; D008545:Melanoma / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine