Comparison of the activity of 2'-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine in vivo. |
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Authors: | W Plunkett L Alexander S Chubb T L Loo |
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Institution: | Department of Developmental Therapeutics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, TX, USA 77 |
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Abstract: | 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 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 () 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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Keywords: | EHNA erythro-9-(2-hydroxy-3-nonyl)-adenine cordycepin 3′-deoxyadenosine DSC DNA synthetic capacity PCA perchloric acid |
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