p53 protein expression in human breast carcinoma: lack of prognostic potential for recurrence of the disease.

Mutations of the p53 gene are now known to be one of the most commonly detected genetic defects among human cancers. Because of its stability, the mutant p53 protein can be detected by immunohistochemical methods. Overexpression of the mutant p53 protein has been suggested as a prognostic indicator for the recurrence of breast cancer. Using a monoclonal antibody to p53, formalin-fixed, paraffin embedded breast cancer tissues retrieved from up to 10 years storage in the archival files were processed for staining. A total of 125 cases was examined p53 overexpression was identified by brown nuclear staining. Clinical parameters studied included estrogen and progesterone receptors, tumor size, nodal status, obesity, stage, and histopathological grade. The only significant association seen for p53 overexpression was with negative estrogen and progesterone receptors. All other clinical parameters studied were independent of p53 overexpression. Thus, p53 overexpression does not appear to be a useful prognostic indicator for recurrence and survival in human breast cancer.

Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo.

BACKGROUND: An inhibitory effect of ascorbic acid (AsA) on melanogenesis has been described. However, AsA is quickly oxidized and decomposed in aqueous solution and thus is not generally useful as a depigmenting agent. OBJECTIVE: Our purpose was to examine the effect on pigmentation of magnesium-L-ascorbyl-2-phosphate (VC-PMG), a stable derivative of AsA. METHODS: Percutaneous absorption of VC-PMG was examined in dermatomed human skin, and its effect on melanin production by mammalian tyrosinase and human melanoma cells in culture was also measured. A 10% VC-PMG cream was applied to the patients. RESULTS: VC-PMG suppressed melanin formation by tyrosinase and melanoma cells. In situ experiments demonstrated that VC-PMG cream was absorbed into the epidermis and that 1.6% remained 48 hours after application. The lightening effect was significant in 19 of 34 patients with chloasma or senile freckles and in 3 of 25 patients with normal skin. CONCLUSION: VC-PMG is effective in reducing skin hyperpigmentation in some patients.

Mechanism of cross-resistance to cisplatin in a mitomycin C-resistant human bladder cancer cell line.

This study was undertaken to elucidate the mechanism(s) of cross-resistance to cisplatin (CDDP) in a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC. The J82/MMC cell line displayed 2- to 3-fold cross-resistance to CDDP and carboplatin when compared to the parental J82/WT cells. Drug uptake studies revealed that cross-resistance to CDDP in the J82/MMC cell line was independent of reduced platinum accumulation. The J82/MMC cell line exhibited approximately a 1.5-fold resistance to cadmium chloride, an indicator for increased metallothionein (MT) content, when compared to the J82/WT cells. Northern blot analysis showed a 2.7-fold higher level of MT-IIA mRNA in the J82/MMC cell line compared with J82/WT. We have reported previously that, whereas glutathione (GSH) level is comparable in these cells, GSH transferase (GST) activity is significantly higher in the J82/MMC cell line compared with J82/WT. Results of the present study showed that the elevated GST activity in the J82/MMC cell line was due to an over-expression of pi-type GST protein. Although buthionine-S,R-sulfoximine (BSO)-induced GSH depletion significantly enhanced CDDP cytotoxicity in both cell lines, the magnitude of potentiation was markedly higher in J82/MMC cells (about 2.1-fold) relative to J82/WT (about 1.6-fold). Our results suggest that cross-resistance to CDDP in the J82/MMC cell line may be due to alterations in cellular thiols.

Metastasis of B16F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis.

Lovastatin (LST) is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme that regulates the biosynthesis of cholesterol. This drug is used clinically to treat patients with hypercholesterolemia. Numerous studies have also suggested an important, if not essential, role of the cholesterol biosynthetic pathway to cell growth and proliferation. In fact, recent studies demonstrating the inhibitory effects of LST on various tumor cells have drawn much attention. We now describe a novel action of LST that inhibited experimental lung metastasis of the highly metastatic B16F10 mouse melanoma in nude mice. Further, when used in in vitro studies, LST pretreatment of B16F10 cells resulted in inhibition of attachment, motility, and invasion, which are key steps in the dynamic sequence of events that comprise the metastatic cascade. Our studies also suggested that the antimetastatic effect of LST on B16F10 cells is probably not mediated by a growth inhibitory action. We submit that these observations identify an antimetastatic agent with potentially useful clinical application.

Correlation between the size of the selenite-exchangeable metabolic pool and total body or liver selenium in rats.

This study explored the quantitative relationship between the size of the selenite-exchangeable metabolic pool (WSe-EMP) and total body or liver Se in rats of varying age and past Se intake. We performed four experiments. In one, weanling rats were fed either a Se-deficient or Se-supplemented diet for 30 d, followed by measurement of WSe-EMP and total body Se. For the other experiments, rats were fed natural sources of Se without added selenite until adult age and then either subjected to acute Se restriction during the 7 d of measurements or maintained on a Se-sufficient diet. For the animals fed the selenite diet, the 7-d average ratio of WSe-EMP:total body Se (Se(end),0) was 0.370 +/- 0.009, which was not significantly different from the corresponding value (0.350 +/- 0.018, P greater than 0.05) for the Se-deficient group. When the group mean values of WSe-EMP were correlated with the corresponding mean values of Se(end),0 for all experiments, we obtained highly linear relations (r2 greater than 0.96). When WSe-EMP for each animal was correlated with the corresponding value of total body endogenous Se (Se(end)) or liver Se(end) (for t = 1 or 7 d), we found equally strong linear relations (r2 greater than or equal to 0.99). We concluded that WSe-EMP accurately reflected total body Se content or the Se content of such organs as liver, regardless of past Se intake, chemical form of Se or age and size of the animals.