TY - JOUR
T1 - Comparison of the activity of 2′-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine in vivo
AU - Plunkett, William
AU - Alexander, Lillie
AU - Chubb, Sherri
AU - Loo, Ti Li
N1 - Funding Information:
The recent availability of EHNAt [l] and dCF [2], two potent inhibitors of adenosine deaminase, has prompted a variety of studies that have demonstrated the potential therapeutic usefulness of these compounds. Coadministration of these deaminase inhibitors with adenosine deaminase-sensitive “normal” nucleosides, such as adenosine or 2’-deoxyadenosine [3,4], or nucleoside analogs, such as ara-A [S, 61, xyl-A [7, S] or cordycepin [5], greatly increases the in vitro cytotoxicity of the latter compounds. The antiviral activity of ara-A in vitro is similarly enhanced in the presence of an adenosine deaminase inhibitor [9-l 11, and the antitumor activity of ara-A [S, 12-l 51, xyl-A [16] and cordycepin [ 171 is increased greatly by coadministration with either EHNA or dCF. Furthermore, in the presence of adenosine, inhibitors of adenosine deaminase depress the blasto-genie response of human lymphocytes [l&23] and monocyte maturation [24] in vitro. Both dCF and EHNA may be effective alone as immunosuppressive agents in uioo [25,26]. Studies on the kinetics of inhibition of partially purified adenosine deaminase -___ _____ *This work has been supported by USPHS Grants CA 14528 and CA 16672, and NC1 contract CM-53773.
PY - 1979
Y1 - 1979
N2 - The inhibition of P388 cell deamination of arabinosyladenine (ara-A) in vivo by the adenosine deaminase inhibitors 2′-deoxycoformycin (dCF) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and their subsequent effects on ara-A metabolism were determined and compared. A single i.p. injection of EHNA (3 mg/kg, 10.9 μmoles/kg) initially inhibited ara-A deamination in vivo by 96 per cent with recovery to 50 per cent of control values within 30 min. In comparison, dCF (0.2 mg/kg, 0.75 μmole/kg) inhibition of ara-A deamination was initially low (4 per cent), but maximized (96 per cent) after 15 min. This inhibition was sustained for 2 hr and did not recover to 50 per cent of control values until after 10 hr. Injected alone, the T 1 2 of ara-A in the peritoneal ascitic fluid was less than 1 min, but was increased to 7 min when injected with EHNA and to 12 min when injected 15 min after dCF. The rate of efflux of ara-A and its metabolites from the peritoneal cavity (T case1 2 = 15-18 min) was not affected significantly by either deaminase inhibitor. Cellulat ara-ATP concentrations were elevated and the extent and duration of inhibition of DNA synthetic capacity were increased identically in cells of mice treated with ara-A and either deaminase inhibitor as compared with those treated with ara-A alone. Sustained deaminase inhibition after intraperitoneal concentrations of ara-A had been diminished by otherwise normal disposition did not augment the biochemically demonstrable activity of ara-A. Therefore, it appears that maintenance of the initial high concentrations of ara-A is the primary function of a deaminase inhibitor in increasing the therapeutic efficacy of this analog.
AB - The inhibition of P388 cell deamination of arabinosyladenine (ara-A) in vivo by the adenosine deaminase inhibitors 2′-deoxycoformycin (dCF) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and their subsequent effects on ara-A metabolism were determined and compared. A single i.p. injection of EHNA (3 mg/kg, 10.9 μmoles/kg) initially inhibited ara-A deamination in vivo by 96 per cent with recovery to 50 per cent of control values within 30 min. In comparison, dCF (0.2 mg/kg, 0.75 μmole/kg) inhibition of ara-A deamination was initially low (4 per cent), but maximized (96 per cent) after 15 min. This inhibition was sustained for 2 hr and did not recover to 50 per cent of control values until after 10 hr. Injected alone, the T 1 2 of ara-A in the peritoneal ascitic fluid was less than 1 min, but was increased to 7 min when injected with EHNA and to 12 min when injected 15 min after dCF. The rate of efflux of ara-A and its metabolites from the peritoneal cavity (T case1 2 = 15-18 min) was not affected significantly by either deaminase inhibitor. Cellulat ara-ATP concentrations were elevated and the extent and duration of inhibition of DNA synthetic capacity were increased identically in cells of mice treated with ara-A and either deaminase inhibitor as compared with those treated with ara-A alone. Sustained deaminase inhibition after intraperitoneal concentrations of ara-A had been diminished by otherwise normal disposition did not augment the biochemically demonstrable activity of ara-A. Therefore, it appears that maintenance of the initial high concentrations of ara-A is the primary function of a deaminase inhibitor in increasing the therapeutic efficacy of this analog.
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U2 - 10.1016/0006-2952(79)90504-5
DO - 10.1016/0006-2952(79)90504-5
M3 - Article
C2 - 426835
AN - SCOPUS:0018372866
SN - 0006-2952
VL - 28
SP - 201
EP - 206
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -