THE RELATIONSHIP BETWEEN THE ANTITUMOR-ACTIVITY AND THE RIBONUCLEOTIDE REDUCTASE INHIBITORY ACTIVITY OF (E)-2'-DEOXY-2'-(FLUOROMETHYLENE) CYTIDINE, MDL 101,731

(E)-2'-Deoxy-2'-(fluoromethylene) cytidine (MDL 101,731) is a new deox ycytidine analog which shows potent antitumor activity against several human tumor models. We previously showed that MDL 101,731 inhibited h uman ribonucleotide reductase (RNR) in HeLa S3 human cervical carcinom a cells. Recently, it has been reported that another deoxycytidine ana log, 2'-deoxy-2'-methylidenecytidine (DMDC) which also inhibits RNR fr om Escherichia coil, does not inhibit RNR in intact L1210 murine leuke mia cells. MDL 101,731 was designed as an inhibitor of RNR, so it is i mportant to know the contribution of the RNR inhibitory activity of th e drug on its antitumor efficacy in vivo. Therefore, we examined the r elationship between the antitumor activity and RNR inhibitory activity of MDL 101,731 using LX-1 human lung carcinoma which was highly sensi tive to this drug. MDL 101,731 showed strong inhibition of RNR activit y in LX-1 lung carcinoma by both i.v. and p.o. administration. Adminis tration of 15 mg/kg i.v. and 30 mg/kg p.o. of MDL 101,731, 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 simi lar 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 deoxycytidin e analog and inhibits DNA polymerase alpha, did not inhibit RNR in LX- 1 lung carcinoma at doses demonstrating antitumor activity. These resu lts indicate that MDL 101,731 exhibited antitumor activity through inh ibition of RNR activity in tumor cells in vivo and the mechanism of an titumor action of MDL 101,731 might be different from those of DMDC an d ara-C, at least in part. [(C) 1998 Lippincott Williams & Wilkins.].