Suppression of C-1300 murine neuroblastoma cell proliferation in tissue culture and tumor growth in vivo by (Z)5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), an irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase.
The effect of the irreversible S-adenosyl-L-homocysteine hydrolase inhibitor, (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), on C-1300 murine neuroblastoma (MNB) cell proliferation in tissue culture and MNB tumor growth in vivo were investigated. MNB cells were incubated with MDL 28,842 at concentrations ranging from 8 x 10(-9) M to 1.6 x 10(-5) M for 3 days, and cell proliferation was determined by use of a CellTiter 96-well Proliferation Assay Kit. In tissue culture, MDL 28,842 inhibited MNB cell proliferation in a concentration-dependent manner, and the IC50 of MDL 28,842 against MNB in tissue culture was 1.8 x 10(-7) M. The response of in vivo tumor growth and host survival to MDL 28,842d was evaluated in a syngeneic mouse tumor model prepared by s.c. implantation of 1 x 10(6) MNB cells into A/J mice. Following palpation of a tumor mass, osmotic minipumps were implanted into each mouse. MDL 28,842 was infused at rates of 1.0 or 1.5 mg/kg/day over a 10-day period and 1.25 mg/kg/day over a 30-day period. The mean survival time of tumor-bearing mice significantly increased from 28.75 +/- 1.06 days (mean +/- 2 SEM) in the control group (diluent infusion) to 39.33 +/- 1.58 days, 44.11 +/- 1.74 days, and 41.0 +/- 1.30 days in the MDL 28,842-treated groups receiving 10-day infusions of 1.0 and 1.5 mg/kg/day or 30-day infusions of 1.25 mg/kg/day, respectively. No significant differences in survival rate were noted between groups receiving 10 vs 30 days of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhang
C
C
Children's Memorial Institute for Education and Research (CMIER), Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL 60614.
Bowlin
T
T
Mirkin
B L
BL
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D043383:Adenosylhomocysteinase; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011336:Probability; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine