sodium-bicarbonate and Cell-Transformation--Neoplastic

Hypoxia and acidosis develop in in situ tumors as cellular expansion increases the diffusion distance of substrates and metabolites from blood vessels deep to the basement membrane. Prior studies of breast and cervical cancer revealed that cellular adaptation to microenvironmental hypoxia and acidosis is associated with the transition from in situ to invasive cancer. We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer.. A total of 37 C57BL/6 TRAMP mice were randomized to a control group or to 1 of 4 treatment groups. In the latter groups 200 mM sodium bicarbonate were added to drinking water starting between ages 4 and 10 weeks.. In all 18 controls prostate cancer developed that was visible on 3-dimensional ultrasound at a mean age of 13 weeks. They died within 52 weeks (median 37). When sodium bicarbonate therapy commenced before age 6 weeks in 10 mice, all reached senescence (age 76 weeks) without radiographic evidence of prostate cancer. Histological sections of the prostates in this cohort showed hyperplasia but no cancer in 70% of mice and minimal well differentiated cancer in the remainder. When therapy commenced after age 6 weeks in 9 mice, prostate cancer development was no different from that in controls.. Immunohistochemical staining for carbonic anhydrase 9 in regions of ductal hyperplasia showed increased expression in controls vs the early treatment group. Regional pH perturbation in in situ tumors may be a simple, inexpensive and effective cancer prevention strategy.

Topics: Acid-Base Equilibrium; Adaptation, Physiological; Animals; Buffers; Cell Hypoxia; Cell Transformation, Neoplastic; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Transplantation; Phenotype; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Sodium Bicarbonate; Transplantation, Heterologous

Clinical (n = 281) and histopathological (n = 141) characteristics of toombak-associated oral mucosal lesions detected in an epidemiological study in northern Sudan in 1992/93 are described. The lesional site in the majority of toombak users was the anterior lower labial groove and the lower labial mucosa. 4 degrees (1-4) of clinical severity of lesions, similar to those used to characterise Swedish snuff-dipper's lesion, were applied. An association between the severity of mucosal lesions and a longer lifetime duration (> 10 years) of toombak use was found, but the severity was not related to the daily frequency of the habit. Parakeratosis, pale surface staining of the epithelium and basal cell hyperplasia were commonly observed, but epithelial dysplasia was infrequent (10/141). The most significant observation was a PAS-positive amorphous deposit between the lamina propria and the submucosa, found in 25/141 biopsies. The clinical and histopathological features of toombak lesions are closely similar to Swedish moist snuff-dipper's lesions and this may reflect the high alkalinity of these products, resulting in an alkaline burn on the oral mucosa following chronic exposure. The low prevalence of epithelial dysplasia implies a low risk of malignant transformation. Nevertheless, the high concentrations of tobacco-specific nitrosamines present in toombak, and the high prevalence of oral cancer in Sudan, mandate biopsy and careful histopathological analysis of any such lesions detected in habitues.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkalies; Burns, Chemical; Carcinogens; Cell Transformation, Neoplastic; Epithelium; Female; Humans; Leukoplakia, Oral; Lip; Male; Middle Aged; Mouth Diseases; Mouth Mucosa; Mouth Neoplasms; Nitrosamines; Plants, Toxic; Prevalence; Risk Factors; Sodium Bicarbonate; Sudan; Sweden; Time Factors; Tobacco, Smokeless

Initial studies performed in our laboratory indicated that early passage Syrian hamster embryo (SHE) cells exhibit optimal clonal proliferation when cultured in medium with a sodium bicarbonate concentration of 8.9 mM and pH of 6.70 instead of 44 mM and pH 7.35 as used previously by others. Subsequent studies indicated that morphological transformation frequency induced by benzo[a]pyrene (BP) was also enhanced at pH 6.70 compared to 7.35 and the level of enhancement was affected by cell density and duration of culture. With optimal conditions identified, the carcinogens BP, 3-methylcholanthrene, N-methyl-N'-nitro-N-nitrosoguanidine, 2-acetylaminofluorene and the non-carcinogen anthracene were tested at pH 6.70 and 7.35 in our laboratory and at Microbiological Assoc. Inc. under code. Additionally, the non-carcinogens 4-acetylaminofluorene, and caprolactam were tested in our laboratory. Results from these studies indicate that all carcinogens tested caused a significant increase in morphological transformation frequency compared to controls at pH 6.70. In contrast, only BP caused a significant increase in the morphological transformation frequency at pH 7.35. The non-carcinogens did not significantly increase the morphological transformation frequency compared to controls. Interlaboratory comparisons were in qualitative agreement despite the fact that different lots of serum and hamster cell isolates were used by the two laboratories. However, different dose-response curves for the various chemicals were observed between the two labs. It was also demonstrated that the enhanced morphological transformation frequency is not due to a decrease in culture medium osmolality or Na concentration, a condition which accompanies media with a reduced bicarbonate concentration and pH. These results demonstrate that the chemicals tested, low pH transformation of SHE cells agrees with carcinogenic potential and that assay variability is minimized. The implications of these results regarding use of the SHE cell assay as a short-term test for predicting the carcinogenic potential of chemicals are discussed.

Topics: Animals; Bicarbonates; Carcinogenicity Tests; Cell Transformation, Neoplastic; Clone Cells; Cricetinae; Culture Media; Dose-Response Relationship, Drug; Embryo, Mammalian; Hydrogen-Ion Concentration; Mesocricetus; Osmolar Concentration; Sodium; Sodium Bicarbonate