Nucleoside transport in normal and neoplastic cells.
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have Na(+)-dependent nucleoside transport, although they may also have an NBMPR-sensitive component of transport (Belt, unpublished data).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.
Belt
J A
JA
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Marina
N M
NM
Phelps
D A
DA
Crawford
C R
CR
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D033703:Nucleoside Transport Proteins; D009705:Nucleosides / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D013868:Thioinosine; D012964:Sodium; C001789:4-nitrobenzylthioinosine