Phase I randomized double-blind placebo-controlled single-dose safety studies of Bowman-Birk inhibitor concentrate.

Lilie L Lin,Jeffrey Ware,James Metz,Rosemarie Mick,Ann R Kennedy,Ramesh Rengan,Robert Lustig,Neha Vapiwala

doi:10.3892/ol.2014.1855

Abstract

In previously performed animal studies and Phase I–II human trials, Bowman-Birk inhibitor concentrate (BBIC) appeared to be a promising cancer chemopreventive agent. The present study describes the results of two phase I randomized double-blind placebo-controlled trials performed in male subjects to assess the safety and toxicity of the original and new formulations of BBIC administered in a single dose as a suspension in orange juice. The dose of BBIC varied from 800–2,000 chymotrypsin inhibitor (CI) units. The BBI concentration in the serum samples collected from the subjects was analyzed by a dot-blot analysis procedure using the 5G2 monoclonal antibody, which is specific for reduced BBI. A total of 41 subjects were enrolled, 20 in the initial BBIC study and 21 in the second BBIC study. In these human trials, no clinically relevant changes in hematological or biochemical parameters were observed. Overall, BBIC was found to be well-tolerated. For these BBIC single-dose phase I trials, there was no dose-limiting toxicity for BBIC, even at the highest dose evaluated, and there were no apparent differences between the clinical trial results for the two formulations of BBIC. The bioavailability of BBI in the second clinical trial, which used the new BBIC formulation, was approximately 40 to 43% of the BBI bioavailability reached in the first clinical trial, which used the original BBIC formulation. The observed bioavailability difference was attributed to the different BBIC formulations used in these two clinical trials. These trials demonstrated that BBIC is safe when administered in a single dose of up to 2,000 CI units. Therefore, the results from the two trials indicate that a multi-dose trial of BBIC may be safely performed with doses of up to 2,000 CI units per day.

Highlights

Increasing evidence indicates that individuals with a high dietary intake of soybean‐derived products have low incidence and mortality rates from common cancers in the Western hemisphere, including cancers of the colon, breast and prostate [1]
In phase I clinical trials performed previously, no toxicity was observed when BBI concentrate (BBIC) was orally administered in a single dose of up to 800 chymotrypsin inhibitor (CI) units in patients with premalignant lesions known as oral leukoplakia [13] or in daily doses of up to 800 CI units for 6 months in patients with benign prostatic hyperplasia [14]
Over the dose range of 200‐1,000 CI units per day, BBIC caused a reduction of total oral leukoplakia lesion size that was linearly correlated with increase in dose

Summary

Introduction

Increasing evidence indicates that individuals with a high dietary intake of soybean‐derived products have low incidence and mortality rates from common cancers in the Western hemisphere, including cancers of the colon, breast and prostate [1]. A number of different agents in soybeans may act as cancer chemopreventive agents in human populations [2] These agents include the soybean‐derived protease inhibitor, Bowman‐Birk inhibitor (BBI), inositol hexaphosphate (phytic acid), the sterol, β‐sitosterol, and the isoflavone, genistein, which have been demonstrated to suppress the development of cancer in animal carcinogenesis assay systems. BBI has been shown to have the strongest anticarcinogenic activity in animal carcinogenesis model systems in comparison to other potential cancer chemopreventive agents in soybeans [2]. Like BBI, BBIC inhibits trypsin and chymotrypsin and is anticarcinogenic, as measured by its ability to prevent malignant transformation in vitro and suppress carcinogenesis in vivo (reviewed in 3,9,11,12).

Methods

Results

Conclusion