Article Figures & Data
Figures
- Figure 1
Structural formulas of AZT and 3-methyl-CycloSal-AZTMP.
- Figure 2
Decay of intracellular [3H]AZTTP (A) and total [3H]AZTMP plus [3H]AZTDP plus [3H]AZTTP metabolites (B) as a function of time after removal of [3H]AZT or [3H]CycloSal-AZTMP from the extracellular medium. The CEM cell cultures were loaded for 24 h with 0.09 μM [3H]AZT or 0.07 μM [3H]CycloSal-AZTMP before drug removal from the culture medium.
- Figure 3
Metabolism of [3H]AZT (top) and [3H]CycloSal-AZTMP (bottom) in wild-type (CEM/0; left) and TK-deficient CEM/TK− cell cultures (right) on 2, 6, and 24 h (top panels) or 2, 20, and 44 h (bottom panels) incubation of the cells with radiolabeled drugs at a concentration of 0.07 μM (CycloSal-AZTMP) or 0.09 μM (AZT) of the radiolabeled drugs.
- Figure 4
Proposed activation scheme ofCycloSal-AZTMP.
Tables
- Table 2
Metabolism of [3H]AZT and [3H]CycloSal-AZTMP on 24-h incubation of CEM cells at different initial drug concentrations for 24 h
Initial AZT Concentration [CH3−3H]AZT AZT (fr 2-3)2-a AZTMP (fr 10-11)2-a AZTDP (fr 15-16-17)2-a AZTTP (fr 25-26-27)2-a μM pmol/109cells 0.09 83 8,437 261 444 1 640 41,170 450 860 10 2,800 113,600 590 840 100 34,000 414,000 1,900 2,700 Initial CycloSal-AZTMP Concentration [CH3−3H]CycloSal-AZTMP AZT + Prodrug (fr 2-3)2-a AZTMP (fr 10-11)2-a AZTDP (fr 15-16-17)2-a AZTTP (fr 25-26-27)2-a μM pmol/109cells 0.07 41 4,926 148 331 1 620 36,180 370 650 10 2,500 107,400 650 940 100 32,000 401,000 1,800 1,500 Values are the mean of two of four independent experiments.
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↵2-a The values within parentheses represent the elution times (min) (or fraction numbers) of the metabolites. Each fraction contains 1 ml, collected in 1 min.
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- Table 1
Metabolism of [3H]AZT and [3H]CycloSal-AZTMP in CEM cell cultures in function of incubation time
Time [CH3−3H]AZT (0.09 μM) AZT (fr 2-3)1-a AZTMP (fr 8-9-10)1-a AZTDP (fr 14-15-16)1-a AZTTP (fr 22-23-24)1-a h pmol/109cells 2 80 10,990 313 816 6 112 16,370 412 1,032 24 84 9,473 427 843 48 62 6,868 391 702 72 40 4,187 304 455 [CH3−3H]CycloSal-AZTMP (0.07 μM) AZT + Prodrug (fr 2-3)1-a AZTMP (fr 9-10-11)1-a AZTDP (fr 14-15-16)1-a AZTTP (fr 22-23-24)1-a h pmol/109cells 2 12 171 13 11 6 13 1,215 57 146 24 39 5,475 236 425 48 43 4,786 219 376 72 29 3,304 203 260 Values are the mean of two to four independent experiments.
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↵1-a The values within parentheses represent the elution times (min) (or fraction numbers) of the radiolabeled metabolites. Each fraction contains 1 ml, collected in 1 min.
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- Table 3
Metabolites of 0.09 μM [3H]CycloSal-AZTMP in CEM, MT-4, Molt 4/C8, DAUDI, PBL , and M/M cells after 24-h incubation
Cell Line [3H]CycloSal-AZTMP AZT + Prodrug (fr 2-3)3-a AZTMP (fr 9-10)3-a AZTDP (fr 14-15)3-a AZTTP (fr 22-23)3-a pmol/109cells CEM 39 5,5475 236 425 MT-4 64 2,002 267 385 MOLT 4/C8 111 7,854 357 755 DAUDI 58 11,572 781 1,920 PBL (resting) 5.8 2.6 0.33 0.5 PBL (activated) 17 843 22 33 M/M 23 1,044 28 29 Values are the mean of two to four independent experiments.
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↵3-a The values within parentheses represent the elution times (min) (or fraction numbers) of the metabolites. Each fraction contains 1 ml, collected in 1 min.
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Cell Line [3H]AZT AZT (fr 2-3)4-a AZTMP (fr 9-10-11)4-a AZTDP (fr 15-16-17)4-a AZTTP (fr 24-25-26)4-a pmol/109 cells PBL 3.0 3.6 0.53 0.57 PBL (activated) 30 2,202 38 44 Values are the mean of two independent experiments.
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↵4-a The values within parentheses represent the elution times (min) (or fraction numbers) of the metabolites. Each fraction contains 1 ml, collected in 1 min.
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