Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model.

Diet and lifestyle produce major effects on tumour incidence, prevalence, and natural history. Moderate dietary restriction has long been recognised as a natural therapy that improves health, promotes longevity, and reduces both the incidence and growth of many tumour types. Dietary restriction differs from fasting or starvation by reducing total food and caloric intake without causing nutritional deficiencies. No prior studies have evaluated the responsiveness of malignant brain cancer to dietary restriction. We found that a moderate dietary restriction of 30-40% significantly inhibited the intracerebral growth of the CT-2A syngeneic malignant mouse astrocytoma by almost 80%. The total dietary intake for the ad libitum control group (n=9) and the dietary restriction experimental group (n=10) was about 20 and 13 Kcal x day(-1), respectively. Overall health and vitality was better in the dietary restriction-fed mice than in the ad libitum-fed mice. Tumour microvessel density (Factor VIII immunostaining) was two-fold less in the dietary restriction mice than in the ad libitum mice, whereas the tumour apoptotic index (TUNEL assay) was three-fold greater in the dietary restriction mice than in the ad libitum mice. CT-2A tumour cell-induced vascularity was also less in the dietary restriction mice than in the ad libitum mice in the in vivo Matrigel plug assay. These findings indicate that dietary restriction inhibited CT-2A growth by reducing angiogenesis and by enhancing apoptosis. Dietary restriction may shift the tumour microenvironment from a proangiogenic to an antiangiogenic state through multiple effects on the tumour cells and the tumour-associated host cells. Our data suggest that moderate dietary restriction may be an effective antiangiogenic therapy for recurrent malignant brain cancers.

N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours.

Abnormalities in glycosphingolipid (GSL) biosynthesis have been implicated in the oncogenesis and malignancy of brain tumours. GSLs comprise the gangliosides and the neutral GSLs and are major components of the cell surface glycocalyx. N -butyldeoxynojirimycin (N B-DNJ) is an imino sugar that inhibits the glucosyltransferase catalysing the first step in GSL biosynthesis. The influence of N B-DNJ was studied on the growth and ganglioside composition of two 20-methylcholanthrene-induced experimental mouse brain tumours, EPEN and CT-2A, which were grown in vitro and in vivo. N B-DNJ (200 microM) inhibited the proliferation of the EPEN and CT-2A cells by 50%, but did not reduce cell viability. The drug, administered in the diet (2400 mg kg(-1)) to adult syngeneic C57BL/6 mice, reduced the growth and ganglioside content of subcutaneous and intracerebral EPEN and CT-2A tumours by at least 50% compared to the untreated controls. N B-DNJ treatment also shifted the relative distribution of tumour gangliosides in accordance with the depletion of metabolic substrates. Side effects of N B-DNJ treatment were generally mild and included reductions in body and spleen weights and intestinal distension. We conclude that N B-DNJ may inhibit tumour growth through an effect on ganglioside biosynthesis and may be useful as a new chemotherapy for brain tumours.