Although the mechanisms of therapeutic efficacy of
cytosine arabinoside (
Ara-C) are multifactorial, the pharmacodynamic basis for its cytotoxicity and therapeutic efficacy lies in its intracellular metabolism and the retention of the active metabolite,
Ara-C triphosphate (
Ara-CTP), which is a competitive inhibitor of
DNA polymerase. Additional determinants of
tumor cell sensitivity include Ara-
CMP incorporation into cellular
DNA, the size of the competing normal metabolite,
deoxycytidine/5'-
triphosphate pool, and the heterogeneity in growth kinetics of
tumor cells, S-phase vs cells in other phases of the cell cycle. With high-dose
Ara-C, substantial amounts of
Ara-CTP are formed in phases of the cell cycle. The presence of high intracellular concentration with prolonged retention of
Ara-CTP could lead to the inhibition of cell growth of the cells entering S-phase as a consequence of inhibition of
DNA-polymerase and/or incorporation into cellular
DNA, resulting in a chain termination. Pharmacokinetically,
Ara-C is rapidly eliminated from plasma. In mice, pharmacokinetic parameters of
Ara-C are not sufficient predictors for the observed differences in their in vivo antitumor activity. Although these mice were bearing different
tumor types (L1210
Ara-C sensitive or P-388 relatively more resistant), the observed differences in
tumor response were achieved under identical plasma
Ara-C concentrations and area under the concentration time curve. The observed antitumor activity in L1210 cells is primarily associated with higher
Ara-CTP pools and retention (T1/2 > 4 hr) in
tumor cells as compared with normal bone marrow cells. In the least responsive
tumor (P-388), although
Ara-CTP pools were sufficiently high, retention of the
drug in
tumor cells and in normal cells is poor with a T1/2 < 2 hr. Thus, unlike mice bearing
leukemia L1210 cells, alteration of the mode and dose of administration of
Ara-C in mice bearing P-388 could only result in increased host toxicity with no therapeutic gain. Similarly in patients with acute nonlymphocyte
leukemia (
ANLL), there is no significant correlation between plasma
Ara-C concentration and the intracellular concentrations or retentions of
Ara-CTP. In some patients the highest
Ara-CTP pools in leukemic myeloblast cells are achieved at a lower level of plasma
Ara-C and decrease further with the increase of plasma
Ara-C. Thus, in the in vivo model system and in
ANLL patients with no prior
chemotherapy,
Ara-CTP retention is a critical factor associated with response to this agent, in particular its direct association with duration of complete response.(ABSTRACT TRUNCATED AT 400 WORDS)