The permeation of
nucleosides across the plasma membrane of mammalian cells is complex and mediated by at least five distinct transporters that differ in their sensitivity to inhibitors and in their specificity for
nucleosides. The basic properties and permeant specificity of these transporters are summarized in Table 3. It appears that there may be differences in the distribution of these transporters in
tumors and normal tissues that might be exploited for chemotherapeutic purposes. The human tumor cell lines examined express predominantly the
NBMPR-sensitive equilibrative transporter es which can be blocked by low concentrations of
NBMPR and
dipyridamole. It is reasonable to expect that
tumors with transport properties similar to the CCRF-CEM and Rh28 cell lines (Table 1) that have no detectable
NBMPR-insensitive transport activity will be highly susceptible to the therapeutic approach of combining a transport inhibitor such as
dipyridamole or
NBMPR with an inhibitor of de novo
pyrimidine biosynthesis. On the other hand, this approach to
therapy is unlikely to succeed against
tumors with transport phenotypes similar to the WI-L2 cell line that may permit the salvage
nucleosides in the presence of these inhibitors. The majority of
tumor cells examined, however, fall between these extremes, and it is not yet known what level of
NBMPR-insensitive transport activity can be tolerated without seriously compromising this therapeutic approach. With respect to normal tissues, the mature absorptive cells of the intestine have predominantly Na(+)-dependent
nucleoside transporters that are insensitive to
NBMPR and
dipyridamole. The proliferating crypt cells also appear to have Na(+)-dependent
nucleoside transport, although they may also have an
NBMPR-sensitive component of transport (Belt, unpublished data). Bone marrow granulocyte-macrophage progenitor cells also appear to have one or more concentrative
nucleoside transporters. Thus these tissues, which are most vulnerable to the toxicity of
antimetabolites, may be able to salvage
nucleosides in the presence of inhibitors of equilibrative transport and be protected from the toxicity of de novo synthesis inhibitors. It is likely, however, that a successful application of this therapeutic approach will require the analysis of the
nucleoside transport phenotype of individual
tumors in order to identify those patients that may benefit from such
therapy. Since the development of
antibodies and
cDNA probes for the various
nucleoside transporters is currently underway in several laboratories, it is likely that analysis of the
nucleoside transport phenotype of
tumors from biopsy material will be feasible in the future.