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 inh ibitor, (Z)-5'-fluoro4', 5'-didehydro-5'-deoxyadenosine (MDL 28,842), on C-1300 murine neuroblastoma (MNB) cell proliferation in tissue cult ure and MNB tumor growth in vivo were investigated. MNB cells were inc ubated 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 us e of a Celltiter 96-well Proliferation Assay Kit. In tissue culture, M DL 28,842 inhibited MNB cell proliferation in a concentration-dependen t manner, and the ICS, 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 surviva l to MDL 28,842(d) was evaluated in a syngeneic mouse tumor model prep ared by s.c. implantation of 1 x 10(6) MNB cells into A/J mice. Follow ing palpation of a tumor mass, osmotic minipumps were implanted into e ach mouse. MDL 28,842 was infused at rates of 1.0 or 1.5 mg/kg/day ove r a 10-day period and 1.25 mg/kg/day over a 30-day period. The mean su rvival 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 significa nt differences in survival rate were noted between groups receiving 10 vs 30 days of drug treatment. In all groups treated with MDL 28,842, transverse tumor diameters following a 10-day infusion were significan tly reduced from 23.92+/-1.27 mm in controls to 10.36+/-1.09 mm in the group receiving 1.0 mg/kg/day, 9.36+/-0.72 mm in the group administer ed 1.5 mg/kg/day, and 11.2+/-1.59 mm in the group treated with 1.25 mg /kg/day for 30 days. These data demonstrated that MDL 28,842 significa ntly suppresses MNB tumor growth in vitro and in vivo and also prolong s host survival time in tumor-bearing A/J mice. Nucleoside analogues t hat selectively and irreversibly inhibit AdoHcy hydrolase hold promise as potential chemotherapeutic agents for tumors of neuroectodermal or igin.