Dose-dependent inhibition of large intestinal cancer by inositol hexaphosphate in F344 rats.
We have previously reported that inositol hexaphosphate (InsP6) inhibits mitosis and large intestinal cancer (LIC) in F344 rats and CD1 mice when given as 1 or 2% solution in drinking water at the unadjusted pH of 11.3. The purpose of this study was to determine whether InsP6 (i) shows a dose-response inhibition of LIC, and (ii) retains its anti-neoplastic effect at physiological pH. Since InsP6 is known to be a chelator of divalent cations, in preparation for putative clinical trials in humans, we also looked at the mineral bioavailability. F344 rats were fed 0.1% (pH 10.8), 1% (pH 11.3) and 1% (pH 7.4) Na-InsP6 in drinking water. Two weeks following the beginning of InsP6 supplementation, rats were given six injections of azoxymethane (AOM) at a dose of 8 mg/kg body wt/week and were killed 30 weeks following the last injection. Compared to the untreated control rats injected with AOM, 1% InsP6 (pH 11.3) reduces tumor prevalence by 52.2% (P less than 0.01), tumor frequency by 55.8% (P = 0.001) and tumor size by 62.3% (P = 0.001); 0.1% InsP6 showed a lesser reduction in tumor prevalence (21%) but a greater reduction in tumor size 71% (P = 0.001). While there was no significant difference in tumor prevalence and frequency between the two pH groups, the tumor size following 1% InsP6 (pH 7.4) was the smallest (65% smaller than those of pH 11.3, P less than 0.005). There was no significant difference in the serum Mg2+, Ca2+, Fe2+ and Zn2+ level between control rats and those treated with 1% InsP6. We therefore demonstrate that InsP6 (i) is consistently anti-neoplastic for LIC in a dose-dependent manner, (ii) retains its anti-neoplastic activity at physiological pH and (iii) has no demonstrable toxic effect on long-term administration as evident by body wt data and serum mineral levels.
Ullah
A
A
Department of Pathology, University of Maryland, School of Medicine, Baltimore 21201.
Shamsuddin
A M
AM
D000818:Animals; D001397:Azoxymethane; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D007420:Intestine, Large / Q000187:drug effects; D007501:Iron / Q000097:blood; D008274:Magnesium / Q000097:blood; D010833:Phytic Acid / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D015032:Zinc / Q000097:blood
D010833:Phytic Acid; D007501:Iron; D008274:Magnesium; D015032:Zinc; D001397:Azoxymethane; D002118:Calcium