The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice.

Folic acid deficiency (FA-) augments DNA damage caused by alkylating agents. The role of DNA repair in modulating this damage was investigated in mice. Weanling wild-type or 3-methyladenine glycosylase (Aag) null mice were maintained on a FA- diet or the same diet supplemented with folic acid (FA+) for 4 weeks. They were then treated with methyl methanesulfonate (MMS), 100mg/kg i.p. Six weeks later, spleen cells were collected for assays of non-selected and 6-thioguanine (TG) selected cloning efficiency to measure the mutant frequency at the Hprt locus. In wild-type mice, there was no significant effect of either MMS treatment or folate dietary content on splenocyte non-selected cloning efficiency. In contrast, non-selected cloning efficiency was significantly higher in MMS-treated Aag null mice than in saline treated controls (diet-gene interaction variable, p=0.04). The non-selected cloning efficiency was significantly higher in the FA+ diet than in the FA- diet group after MMS treatment of Aag null mice. Mutant frequency after MMS treatment was significantly higher in FA- wild-type and Aag null mice and in FA+ Aag null mice, but not in FA+ wild-type mice. For the Aag null mice, mutant frequency was higher in the FA+ mice than in the FA- mice after either saline or MMS treatment. These studies indicate that in wild-type mice treated with MMS, dietary folate content (FA+ or FA-) had no effect on cytotoxicity, but FA- diet increased DNA mutation frequency compared to FA+ diet. In Aag null mice, FA- diet increased the cytotoxic effects of alkylating agents but decreased the risk of DNA mutation.

Vitamin E but not St. John's wort mitigates leukopenia caused by cancer chemotherapy in rats.

Dietary supplements are used by most patients with cancer. As nutraceuticals can interact with many drugs, this study investigated the effect of herbal remedies and vitamins on the toxicity of representative cancer chemotherapeutic agents. Fisher 344 rats were fed a standard cereal-based diet or the same diet with additional vitamin E in low (50 mg/kg) or high (750 mg/kg) concentrations, or with added St. John's wort (400 mg/kg). The LD50 was determined after the administration of chemotherapy drugs. Neither low or high vitamin E supplements nor St. John's wort significantly changed the LD50 for doxorubicin, docetaxel, or cyclophosphamide. The nadir white blood cell (WBC) count was significantly higher (P = 0.004) after docetaxel in rats supplemented with low-dose vitamin E, but the drop in WBC count from initial to nadir levels (Nfall) was greater in rats fed a diet containing high vitamin E supplementation (P = 0.04). Similarly, the Nfall was greater in the standard and high vitamin E dietary groups than in the low vitamin E group after cyclophosphamide (P = 0.03). No effect of vitamin E or St. John's wort supplementation occurred on doxorubicin pharmacokinetics. Neither vitamin E nor St. John's wort had an important effect on the mitochondrial deoxyribonucleic acid (DNA) damage caused by either doxorubicin or docetaxel. These data suggest that the leucopenia caused by some chemotherapeutic agents can be modified by dietary supplementation with vitamin E, but the effect seems to be dose-dependent. St. John's wort had neither a beneficial nor a detrimental effect on chemotherapy-induced toxicity.

Childhood cryptosporidiosis is associated with a persistent systemic inflammatory response.

Cryptosporidiosis in young children prompts local inflammation in the intestinal tract. We studied a cohort of young children with cryptosporidiosis to determine whether systemic inflammatory responses occur and, if so, to evaluate whether inflammation persists after infection. Cryptosporidiosis was associated with increased levels of interleukin-8 and tumor necrosis factor- alpha systemically, which persisted at 6 months after enrollment. The level of intestinal tumor necrosis factor- alpha was elevated at enrollment, but elevated levels did not persist. Worsening of malnutrition, particularly stunting, was observed after infection. The association of cryptosporidiosis, inflammation, and stunting in children with cryptosporidiosis warrants further evaluation.