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GEOFFREY BURNSTOCK AN. R. ACAD. NAC. FARM.

Phase I and II human trials indicate that ATP has a future place as
a useful anticancer agent. The combination of ATP administration
with other anticancer modalites is beginning to be explored.

Growth of prostate-cancer cells in vitro is inhibited by up to 90%
by ATP via P2 receptors, although it is not yet clear which subtype
mediates this effect and whether it is a directly antiproliferative effect
or a proapoptotic effect (28). Phase I clinical trials have shown that
ATP infusion in patients with advanced cancer is feasible, but is
limited by chest tightness and dyspnoea, probably due to conversion
to adenosine.

A phase II trial has been carried out in patients with non-small
cell lung cancer, showing that intravenous ATP administered for 96
hours at 4-week intervals reduced weight loss and improved muscle
strength and quality of life, as well as inducing cancer cell death (4).

A combination of interferon-? and ATP is being explored for the
treatment of acute myeloid leukaemia. ATP induced irreversible
damage of leukemic cells without injuring normal hemopoietic stem
cells, and it was suggested that it could be useful for purging the
residual leukaemic cells in autologous bone marrow transplantation.
Extracellular ATP suppresses proliferation and induction of
differentiation of human HL-60 leukaemia cells, partly mediated by
adenosine (after breakdown of ATP) and partly by ATP. P2X7 receptor
expression in the evolutive form of chronic ß lymphocyte leukaemia
has been identified; ATP decreased proliferation of lymphocytes in
this form of leukaemia. ß-cell chronic lymphocyte leukaemia is
unique in showing a three-fold increased incidence in closely related
family members compared to other lymphoproliferative diseases; a
candidate gene for this familial incidence is the P2X7 gene.

Recent studies from our laboratory have analysed the P2 receptor
subtypes that contribute to ATP suppression of malignant melanomas
(29) in basal and squamous cell tumours (30) and prostate and
bladder cancers (28). In general, P2Y1 and P2Y2 receptors mediate
proliferative or antiproliferative effects, P2X5 receptors mediate cell
differentiation, which in effect is antiproliferative and P2X7 receptors
mediate apoptotic cell death. ATP administration is particularly
effective in treating bladder tumours when combined with the more
commonly used anticancer drug mitomycin.

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