We have used 5'-deoxy-5'-S isobutyl-thioadenosine (
SIBA), an analog of
S-adenosylhomocysteine, alone or in association with a
methionine-depleted diet in order to obtain an antitumoral effect in two different
tumor models: a transplantable rat
rhabdomyosarcoma (RMS-J1) induced by i.m. injection of
nickel and the well-known
Lewis lung carcinoma (3LL) of C57BL/6 mice. Since
SIBA has been reported to inhibit the methyl group transfer from
methionine to
S-adenosylhomocysteine, among other activities, its association with a reduction of methyl donors, achieved by
methionine depletion of the diet (in vivo) or the culture medium (in vitro), should logically lead to an additive effect. In vitro, 3LL and RMS-J1 were sensitive to the cytotoxic effect of
SIBA and were
methionine-dependent for their proliferation. Fibroblast proliferation was not affected by these two treatments alone or in association. In vivo, either
SIBA treatment or a low
methionine diet led to a significant decrease in the metastatic character of these two
tumors; however, local
tumor growth was not significantly affected. The median number of 3LL
metastases counted in the lungs was reduced from 100 to 18 by
SIBA treatment, and to 27 by the low
methionine diet. No additive effect could be detected when the treatments were given simultaneously. RMS-J1-bearing rats treated with
SIBA and fed a low Met diet underwent primary
tumor excision. The median numbers of lung metastatic nodules were 27, 26, 14 and 8 for the control,
SIBA-treated rats,
methionine-deprived rats and rats receiving the combined
therapy. Expressed as percentages 20 per cent were cured, 23 per cent showed a low number of lung
metastases (P less than 10), whereas all the rats in the control group developed more than 10 pulmonary nodules. No cytotoxic effect could be observed on the treated rats. The role of
SIBA and
methionine depletion, as agents interfering with transmethylation processes, in regard to the control of
tumor development, namely metastatic invasiveness, is discussed.