The efficacy of sequential chemoimmunotherapy involving
interleukin-2 (
IL2) in metastatic
melanoma is limited, in part, by the severe toxicity associated with most therapeutic regimens.
Glutathione (GSH), the most prevalent intracellular non-
protein thiol, plays an important role in protecting against cellular injury caused by various
anticancer agents. GSH is also involved in the IL2-induced proliferative activity of immune system cells and some
melanoma cells expressing
IL2 receptors, such as
B16 melanoma cells. The present study investigated the effect of selective manipulation of GSH using the
cysteine prodrug l-2-oxothiazolidine-4-carboxylate (OTZ) on the response of
B16 melanoma to sequential biochemotherapy with
cyclophosphamide (CY) and
IL2. We found that OTZ, by depressing GSH levels, abrogates the in vitro growth-promoting effects of
IL2 on
B16 melanoma cells. The combination of OTZ plus
IL2 in vivo also showed antitumour activity in mice bearing
B16 melanoma liver
metastases, significantly increasing their life span. Schedule dependency between both compounds was found; OTZ given intermittently in combination with daily
IL2 administration was found to be the best therapeutic schedule. We also observed that whereas
IL2 or OTZ alone added to CY resulted in a lower or non-significant improvement in the life span of the mice compared with tolerated doses of CY alone, the addition of both OTZ and
IL2 to CY produced a significantly greater increase in survival than CY alone, and markedly protected mice against CY-induced toxicity, which allowed the administration of otherwise lethal doses of CY, with the CY activity/toxicity ratio being increased by four-fold.