COMBINATION THERAPY WITH A NUCLEAR TYPE-II SITE AGONIST AND 5-FLUOROURACIL - INHIBITION OF MAMMARY-TUMOR GROWTH

Abstract

Methyl p-hydroxyphenyllactate (MeHPLA) is an endogenous ligand for nuclear type II sites which apparently regulates cellular growth and proliferation through this binding interaction. Occupancy of type II sites by MeHPLA agonists such as dihydroxybenzylidene acetophenone (DHBA), 2,6-bis ([3,4-dihydroxyphenyl]-methylene) cyclohexanone (BDHPC) and 2,6-bis ([3-methoxy-4-hydroxyphenyl]-methylene)cyclohexanone (BMHPC) is directly correlated with the inhibition of malignant cell proliferation. Most importantly, these compounds inhibit mammary tumor growth in vivo with minimal non-specific cytotoxicity. Therefore, combination therapy with MeHPLA agonists plus standard anti-neoplastic agents such as 5-Fluorouracil (FU) may result in tumor growth inhibition with minimal non-specific cytotoxicity. The results of these studies demonstrated that low doses of BMHPC (2 mug/mL) and FU (0.2 mug/mL) failed to significantly affect MCF-7 human breast cancer cell proliferation. However, combination therapy with these sub-inhibitory doses of BMHPC plus FU resulted in significant inhibition of cell proliferation in vitro, suggesting that BMHPC acts in an additive or synergistic fashion with FU to inhibit MCF-7 cell proliferation. Similarly, when orally administered to mice at a dose level of 50 mug/mL drinking water, neither BMHPC or FU alone substantially inhibited the growth of estrogen-independent transplantable mammary tumors. However, combination therapy with BMHPC plus FU antagonized tumor growth and no significant treatment effects were observed on fluid consumption or the body weights of these animals. These results demonstrate that MeHPLA agonists such as BMHPC are capable of acting additively or synergistically with FU to maintain therapeutic response with reduced non-specific systemic toxicity.