THE RELATIONSHIP BETWEEN THE ANTITUMOR-ACTIVITY AND THE RIBONUCLEOTIDE REDUCTASE INHIBITORY ACTIVITY OF (E)-2'-DEOXY-2'-(FLUOROMETHYLENE) CYTIDINE, MDL 101,731
J. Kanazawa et al., THE RELATIONSHIP BETWEEN THE ANTITUMOR-ACTIVITY AND THE RIBONUCLEOTIDE REDUCTASE INHIBITORY ACTIVITY OF (E)-2'-DEOXY-2'-(FLUOROMETHYLENE) CYTIDINE, MDL 101,731, Anti-cancer drugs, 9(7), 1998, pp. 653-657
(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.].