Use of Dietary Isoflavones to Enhance the Antitumor Effect of Chemotherapy for Pediatric Brain tumors:

Children younger than 3 years of age with medulloblastomas who undergo postoperative chemotherapy to delay craniospinal radiation and its resulting neurotoxicity exhibit improvement in overall survival and neuropsychological development. These children are, however, at increased risk for chemotherapy treatment sequelae such as congestive heart failure, bone marrow suppression, kidney failure and secondary malignancies. Research on the use of novel chemotherapeutic agents with fewer side effects is justified.

One group of such agents is the isoflavones, part of the family of receptor tyrosine kinase (RTK) inhibitors. As the most anticarcinogenic and antiproliferative members of this family, the isoflavones genistein and daidzein occur naturally at high concentrations in soybeans and soy-protein foods. Reports on the experimental in vitro and in vivo use of isoflavones have shown encouraging results in blocking malignant transformation, growth and invasiveness of a number of human tumors such as breast cancer, colorectal carcinoma, glioblastoma multiforme and leukemia. In the majority of these studies, however, the effective genistein concentrations are much higher than genistein's physiologic plasma levels following consumption of a soy-based diet or formula.

Genistein accounts for nearly 65% of isoflavones found in soy-formula. Although genistein bioavailability of soymilk in children is still under investigation, a series of human trials has shown isoflavone genistein plasma levels of 3 to 6 mM following oral intake of soymilk formulations in adults and infants. These low blood levels may not justify the use of dietary isoflavones in their current form as sole chemotherapeutic agents for childhood brain tumors. Nevertheless, we have shown that even at such low concentrations when combined with other standard chemotherapy, such as cisplatin and vincristine, genistein strongly enhances the antitumor effect of chemotherapy for a common childhood brain tumor called medulloblastoma.

The primary clinical significance of this finding is that low-dose genistein can enhance the therapeutic effect of cisplatin or vincristine without increasing the risk of renal and bone marrow toxicity, which are the limiting factors with use of these agents. This is particularly true for the pediatric population, where chemotherapy may be more harmful.