(E)-2'-deoxy-2'-(fluoromethylene)
cytidine (MDL101,731) is a new
deoxycytidine analog which shows potent antitumor activity against several human
tumor models. We previously showed that MDL101,731 inhibited human
ribonucleotide reductase (RNR) in HeLa S3 human cervical
carcinoma cells. Recently, it has been reported that another
deoxycytidine analog,
2'-deoxy-2'-methylidenecytidine (DMDC) which also inhibits RNR from Escherichia coli, does not inhibit RNR in intact L1210 murine
leukemia cells. MDL101,731 was designed as an inhibitor of RNR, so it is important to know the contribution of the RNR inhibitory activity of the
drug on its antitumor efficacy in vivo. Therefore, we examined the relationship between the antitumor activity and RNR inhibitory activity of MDL101,731 using LX-1 human lung
carcinoma which was highly sensitive to this
drug. MDL101,731 showed strong inhibition of RNR activity in LX-1 lung
carcinoma by both i.v. and p.o. administration. Administration of 15 mg/kg i.v. and 30 mg/kg p.o. of MDL101,731, doses which showed almost the same degree of antitumor activity against LX-1 lung
carcinoma on a daily 5 day schedule, caused a similar degree and similar kinetics of inhibition of RNR in LX-1 lung
carcinoma at least for 12 h after administration. On the other hand, DMDC as well as 1-beta-D-arabinofuranosyl-cytosine (
ara-C), which is a well-known
deoxycytidine analog and inhibits
DNA polymerase alpha, did not inhibit RNR in LX-1 lung
carcinoma at doses demonstrating antitumor activity. These results indicate that MDL101,731 exhibited antitumor activity through inhibition of RNR activity in
tumor cells in vivo and the mechanism of antitumor action of
MDL 101,731 might be different from those of DMDC and
ara-C, at least in part.