Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine.

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi's sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.

Gender differences in renal growth and function after uninephrectomy in adult rats.

BACKGROUND: It is known that compensatory renal growth (CRG) following unilateral nephrectomy (UNX) increases both the size of the kidney and its functional capacity; however, few studies have investigated whether differences in CRG exist between the sexes. Our study examined the sex-related differences in remnant kidney growth and function two months following UNX. METHODS: Adult male and female Wistar rats underwent either left UNX or sham operation and recovered for 8 to 10 weeks. Another group of female rats underwent ovariectomy (Ox), with vehicle, estrogen, or testosterone replacement: two-weeks postsurgery animals underwent UNX and recovered for 8 to 10 weeks. Metabolic studies, acute renal function studies [response to acute saline volume expansion (2 to 4% of body wt) or phosphate (Pi) infusions in thyroparathyroidectomized rats (to determine the transport maximum (TmPi)], and renal morphology were assessed at the end of the experimental period. RESULTS: Two months post-UNX, male remnant kidneys grew 114+/-7% of their excised kidney weight (KW), whereas female remnant kidneys grew only 57+/-4% (P<0.05). There was a significant increase in the glomerular volume of male remnant kidneys (126.2+/-13.4%, P<0.001) compared with control kidney volume, whereas there was no change in glomerular volume in female remnant kidneys (20.2+/-16.1%, P = NS). There was also glomerular and tubular damage in the male remnant kidneys, whereas female remnant kidneys were intact. Studies in Ox female rats supplemented with gonadal steroids determined that testosterone is the driving force for the enhanced remnant kidney growth and glomerular hypertrophy. Renal function studies determined that UNX males had significantly higher glomerular filtration rates (GFRs) than UNX females, although the GFR/single KW was not different between the sexes, indicating a proportional increase in GFR. Basal urinary sodium excretion and urine flow rates were significantly higher in anesthetized UNX rats than their sham-operated controls, and urinary sodium excretion and urine flow rates in UNX males were significantly higher than in UNX females. Both male and female UNX rats responded to volume expansion with an exaggerated initial sodium and urine excretion compared with their controls. Phosphate handling was not altered in UNX male rats; however, UNX female rats had increases in fractional Pi excretion that were associated with significant reductions in the maximum capacity for Pi reabsorption (2.10+/-0.07 vs. 3.43+/-0.24 micromol/ml GFR in female controls, P<0.0001). This difference was also observed in Ox rats treated with estrogen and testosterone (2.31+/-0.07 vs. 3.12+/-0.11 micromol/ml GFR, P<0.0007). CONCLUSIONS: These findings indicate that sexual dimorphism exists in remnant kidney growth and function two months following UNX. Indeed, morphological abnormalities and impairment in renal phosphate handling are affected by gonadal steroids by two-months post-UNX. The fact that renal Pi transport was reduced in female but not male UNX rats may also have important implications during periods of high metabolic demand for phosphate in the female.

[Clinical experience with alpha blockers and calcium antagonists in the perioperative treatment of pheochromocytoma]. / Esperienza clinica con alpha-bloccanti e calcioantagonisti nel trattamento perioperatorio del feocromocitoma.

This study aims to value the efficacy of the association between alpha-blockers and calcium channel-blockers, administered per os, in the reduction of preoperative preparation in patients with phaeochromocytoma and the calcium channel-blockers utility when are administered e.v. in the control of development of arterial paroxysmal hypertension during surgical manipulations. The trial had been conducted on 5 patients which have undergone the operation, before the operation we administered per os nifedipine and phonoxybenzamine for 8 days and during the operation we administered diltiazem e.v. The association between alpha-blockers and calcium-blockers per os, has reduced the preparation stage and has controlled the pressure parameters during the preoperative treatment. When we utilized diltiazem during the operation, we haven't note a good hemodynamic stability; these results are opposed to Tokioka's. Calcium channel-blockers and alpha-blockers seem to be a good therapy in the preoperative preparation of patients with phaeochromocytomas and they seem to be able to take fastly the standard of preoperative preparation.

Leucovorin rescue of enteric lesions induced by high-dose methotrexate: a time-related study in mice.

In this study, different groups of mice were treated with a single high-dose of methotrexate or with a leucovorin-methotrexate association, and the changes in structure and cell types of the small intestine were studied histologically. The results suggested that leucovorin rescue diminished the degree of mitotic abatement induced by methotrexate in the first days after treatment, with better preservation of enteric structures and the cell type ratio.

Pulmonary toxicity in mice after high-dose methotrexate administration with and without leucovorin rescue.

Interstitial lung lesions were induced in mice by high-dose methotrexate with high frequency. They appeared early after treatment; their onset, evolution and recovery parallelled those of lesions to the hemopoietic tissues and the intestine. The pathogenesis of methotrexate lung toxicity in mice is discussed. Leucovorin rescue was ineffective in preventing the lung lesions induced by high-dose methotrexate.

Immunopotentiation of anticancer chemotherapy by Candida albicans, other yeasts and insoluble glucan in an experimental lymphoma model.

Several yeast species in the genera Candida, Saccharomyces and Cryptococcus showed powerful immunoadjuvant, chemotherapy-synergic effects against a histocompatible, virus-induced murine lymphoma. Sensitizing and booster intraperitoneal injections of 2 x 10(7) yeast cells on days -14 and +1 (with respect to tumor challenge on day 0) followed by treatment with antiblastic drugs (on day +5) were required to elicit optimum activity. The antitumor effect was not markedly influenced by the morphological growth form of merthiolate-inactivated C. albicans nor by the nature of the carbon source in the growth medium, except for C. albicans cells grown in a medium containing stearic acid, which were not effective. These cells had a higher ratio of soluble to insoluble cell wall components, as compared to glucose-grown cells, but this finding alone could hardly explain the lack of antitumor effects. Previous observations, suggesting that the alkali-acid insoluble beta-glucan (in the form of cell wall ghosts) is the only component of yeast cell walls endowed with antitumor activity comparable to that of whole cells, were confirmed and extended; the soluble mannan and glucan-protein fractions were unable to replace whole cells and glucan ghosts even as sensitizers or as boosting agents.