Morpholino-
disiloxane (ALIS-409) and piperazino-
disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of
cancer cells. In the present study, the effects of
ALIS-409 and
ALIS-421 compounds were investigated on
cancer promotion and on co-existence of
tumor and normal cells. The two compounds were evaluated for their inhibitory effects on Epstein-Barr virus immediate-early
antigen (
EBV-EA) expression induced by tetradecanoyl-
phorbol-
acetate (TPA) in Raji cell cultures. The method is known as a primary screening test for antitumor effect, below the (IC50) concentration.
ALIS-409 was more effective in inhibiting
EBV-EA (100 μg/ml) and
tumor promotion, than
ALIS-421, in the concentration range up to 1000 μg/ml. However, neither of the compounds were able to reduce
tumor promotion significantly, expressed as inhibition of TPA-induced
tumor antigen activation. Based on the in vitro results, the two disiloxanes were investigated in vivo for their effects on mouse skin
tumors in a two-stage mouse skin
carcinogenesis study. The application of dimethyl-
benzanthracene (DMBA; 390 nmol) as a
tumor initiator was followed by exposure to TPA (1.7 nmol/l) as a
tumor promoter. The experiments showed that
ALIS-409 at a concentration of 85 nmol/l had a weak
EBV-EA inhibitory effect in vitro and a moderate antitumor activity, compared to the positive control of DMBA plus TPA-treated mice. Flow cytometry by differential staining demonstrated interactions in co-cultures of MCF7
breast cancer and MRC5 human lung fibroblasts. The growth rate of
tumor cells in mixed populations of MCF7
breast cancer and MRC5 normal fibroblast cells was reduced in the presence of
ALIS-409, as compared to the control non-treated cell populations. The two disiloxanes were moderately-effective in
chemoprevention in DMBA-induced and TPA-promoted in vivo
tumor formation. Authors suggest that the inhibition of
tumor cell and fibroblast interaction by
ALIS409 might have some perspective in the development of anti-stromal
therapy.