Enhancement of the antineoplastic effect of anticarcinogens on benzo[a]pyrene-treated Wistar rats, in relation to their number and biological activity.

Naturally occurring anticarcinogens, such as vitamins C and E, and the microelement selenium were found to inhibit the induction of benzo[a]pyrene-induced malignant tumors in Wistar rats to various extends. The antineoplastic effect of the tested anticarcinogens is gradually increased according to the number of inhibitors selected. To date the maximum action against malignancy is manifested by use of the above three inhibitors. In the group of rats receiving vitamins C, E and selenium, the prolongation of life induced by adding more than one anticarcinogen to the treatment regime reached, and in some cases surpassed, the normal life expectancy of the rats. It is expected that by adding even more anticarcinogens, the antineoplastic potency (Ap) of the inhibitors will be further improved. These results encouraged us to conduct a clinical trial in terminal human cancer cases, in conjunction with the usual treatments of surgery or chemotherapy and irradiation.

Dose-related preventive and therapeutic effects of antioxidants-anticarcinogens on experimentally induced malignant tumors in Wistar rats.

A combination of antioxidants-anticarcinogens, consisting of vitamins C and E, selenium and 2-mercaptopropionyl glycine (2-MPG), was administered orally for the prevention (PRG) and treatment (TRG) of benzo(a)pyrene (BaP)-induced malignant tumors (leiomyosarcomas), in Wistar rats. In order to evaluate dose-related effects, a low dose vitamin (0.15 g/kg b.w. per day of vit.C and 0.05 g/kg b.w. per day of vit.E) and a high dose (1.5 g/kg b.w. per day of vit.C and 0.5 g/kg b.w. per day of vit.E) combination was administered, in prevention and treatment groups. Selenium was administered in doses of 2 microg/kg b.w. per day and 2-MPG in 15 mg/kg b.w. per day, in all groups. Daily estimations of 24 h urine volume levels of thiobarbituric acid reacting substances (MDA) were performed in 20 animals, divided into a control group, a BaP-injected group, a tricapryline-injected group and a BaP-injected and treated by the low dose combination group. Results revealed that the low dose combination failed to exert any beneficial effect on mean survival time of animals treated either preventitively or therapeutically. An increased number of animals bearing a second (lung) tumor was, in addition, found in autopsy and histological examination in the low dose combination (PRG and TRG) and the high dose TRG groups. The high dose combination groups manifested a significant prolongation of the mean survival time of animals; complete remission of tumors developed in 16.8% of the animals in the treatment group and a 5.2% prevention of tumor formation in the preventive group, without any evidence of an increased number of double tumor formation in the PRG group. Urine MDA increased significantly in animals injected by BaP during the first 10 days and since the 90th day (formation of palpable tumors) after injection, in relation to control and tricapryline-injected groups. Complete prevention of urine MDA-increased values was obtained in BaP-injected and treated by the low dose combination animals. Results indicate that high doses (megadoses) of the antioxidant-anticarcinogen vitamins C and E in combination with carefully selected other antioxidants possessing supplementary actions, are probably needed in order to achieve a sufficient prevention and treatment of malignant diseases.

Inhibition of benzo(a)pyrene carcinogenesis in rats with vitamin C.

The s.c. infection of 10 mg benzo(a)pyrene dissolved in 1 ml tricaprylin induced in Wistar rats local malignant tumors, such as fibrosarcoma, rhabdomyosarcoma, and polymorph cell sarcoma. The growth of the tumors was relatively rapid, reaching weights of 140-155 g before rats died 142-168 days after the administration of the carcinogen. On the contrary, under the same experimental conditions, high doses of Vitamin C about 525 mg/day/rat administered orally in drinking water (total amount of Vitamin C 55 g/rat corresponding to 40% of their body weight ) inhibited to a great extent the benzo(a)pyrene carcinogenesis. Only one slowly growing rhabdomyosarcoma (13 g of weight) was developed showing characteristic damage of malignant cells and partial replacement of the neoplastic area with granuloma tissue. The significance ov Vitamin C for cancer prevention and treatment is discussed.

Separation of the nucleus from the cytoplasm of frog, chicken and trout erythrocytes by means of high doses of vitamin B12.

The effect of high doses vitamin B12 on the nucleus-bearing erythrocytes in the peripheral blood of the frog, chicken and trout has been investigated. The i.p. and i.m. injection of 5 mg B12/animal, caused the separation of the nucleus from the cytoplasm of the erythrocytes to various degrees. The most pronounced effect was observed in trouts, where 75% of the erythrocytes lost their cytoplasm. Frog and chicken were less susceptible to the denucleating effect of B12. About 10-15% of the frog and chicken erythrocytes lost their cytoplasm 7-8 weeks after the B12 injection.

Serum selenium levels in healthy adults and its changes in chronic renal failure.

In this study the serum selenium levels of 500 healthy Greeks and 225 patients with chronic renal failure (CRF) were measured using Watkinson's method. The patients were treated either conservatively or by peritoneal dialysis or haemodialysis. We found that the levels were in an intermediate position compared to those of other Europeans. Selenium levels were also found to increase significantly with age. No difference was detected between male and female patients. A statistically significant drop was observed in CRF patients compared to age matched controls. This drop was smaller in patients treated conservatively than in those treated by peritoneal dialysis. A further drop was observed in patients under haemodialysis.

Litholytic agents with bacteriostatic properties in conservative treatment of urolithiasis.

Litholytico-bacteriostatic agents such as ethylenediaminetetraacetic acid (EDTA) can be used for direct dissolution of calcium and magnesium containing urinary stones. By means of a double-channel catheter (Timmermann) and the corresponding technique a direct irrigation of the kidney cavities with EDTA solutions was possible, without any serious side effects (instrumental stone chemolysis method). It must be pointed out that the instrumental chemolysis can be clinically applied only by a specialised scientific staff, and improvisation may cause serious complications; further development of new potential litholytico-bacteriostatic agents is necessary in order to increase effectiveness of the method. Some clinical results are reported concerning the indications for this method by X-ray illustrations of successfully treated cases.

[Prevention of 3,4-benzpyrene carcinogenesis by naturally occurring and synthetic compounds]. / Verhinderung der 3,4-Benzopyren-Kanzerogenese

The carcinogenic action of 3,4-benzpyrene (3,4-BP) can be reduced or completely inhibited by the presence of substances which occur in the animal organism and also by compounds prepared synthetically. Experiments in female mice have shown that the addition of some unsaturated aliphatic dicarboxylic and tricarboxylic acids, thiols or biogenic amines to 3,4-benzyprene solutions causes a slowing down of the tumor induction or complete blockade of the tumor development. The same 3,4-BP solutions without the addition of the substances mentioned produced malignant tumors in the mice almost without exception.

Prevention of 3,4-benzopyrene carcinogenesis in presence of putrescine.

The 3,4-Benzopyrene (3,4-BP) carcinogenesis can be postponed or even completely inhibited in the presence of Putrescine (P). A single s.c. injection of 2.52 mg 3,4-BP in 0.5 ml tricaprylin on female mice (NMRI-strains, 4--5 weeks old, 20--25 g of body weight) induced locally malignant tumors (sarcomas and carcinomas) up to 97% of the animals treated. (132 mice with tumors from 136 animals treated). Animals injected with 3,4-BP plus 10 mg putrescine showed a considerable reduction of tumor incidence. Only three from 38 mice treated developed tumors (8%). The prevention of tumor could not be further improved with higher putrescine amounts, for example 15 mg and 20 mg P. These concentrations were moreover toxic to the animals. Histologically, the tumors developed in the presence of putrescine were rather poor in malignant cells and mitoses were also rare, in contrast to the usual 3,4-BP tumors which were rich in polymorph cells and mitoses.

Treatment of cystinuria with Thiola (alpha-mercaptopropionyl glycine).

Nine cystinuric patients (8 females and 1 male) with recurrent L-cystine stone formation have been treated since 1971 with the new drug Thiola (alpha-mercaptopropionyl glycine). Thiola was found to be more effective than D-penicillamine in dissolving L-cystine. In two case a partial dissolution was observed after 20 months of Thiola administration. In four cases further stone growth was stopped. In the last two cases stone growth occurred even after administration of Thiola. Tolerance of the drug was good, and no serious effects were observed sufficient to interrupt treatment.

Selenium and haemodialysis: serum selenium levels in healthy persons, non-cancer and cancer patients with chronic renal failure.

In 40 healthy persons, 11 nondialyzed uremic patients and 27 dialyzed uremic patients, of whom 4 also had cancer, the selenium concentration in serum was determined. The mean serum selenium concentration in healthy persons was 13.6 +/- 0.8 micrograms/dl, in nondialyzed patients 11.9 +/- 1.9 micrograms/dl and in dialyzed uremic patients 11.3 +/- 1.0 micrograms/dl. There was a significant statistical difference between healthy persons and uremic patients (p less than 0.001), but not between dialyzed and nondialyzed uremic patients. The subgroup of cancer patients on hemodialysis also had low serum selenium concentrations. The possible role of low selenium levels as one of the factors responsible for the increased incidence of malignancy in patients with chronic renal failure is supported by several facts such as: low serum selenium levels detected in patients with malignant diseases; the higher cancer incidence in inhabitants of low-selenium areas, and the known ability of selenium to inhibit many types of experimental carcinogenesis.

[The use of mercapto-propionyl-glycine in the treatment of cystine lithiasis (author's transl)]. / L'emploi de la mercapto-propionyl-glycine (M.P.G.) dans le traitement des lithiases cystiniques. A propos de 21 cas.

The authors report the first results of the use of mercaptopropionyl-glycine (M.P.G.) in the solubilising and preventive treatment of cystine lithiasis. This substance results in the formation of a soluble cystine M.P.G. complex. It increases the solubility of cystine much more than D-penicillinamine. Twenty one cases of cystinuric cystine lithiasis were treated in this way, combined with forced diuresis, alkalinisation of the urine and uricolytic treatment. In 4 of their 21 patients, calculi disappeared completely, whilst in another 3 they decreased in size. Recurrence of lithiasis was avoided in 20 patients out of 21. These impressive results are similar to those in the brief literature concerned with the substance. Toxicity is virtually nil and its efficacy make this the drug par excellence for cystine lithiasis.

Metabolic disturbances in cystinuria.

Metabolic investigations were made in 21 cystinuric patients. The results showed a low output of urinary phosphorus and an increase of plasma IgG. These findings and the presence of uric acid in the urine, even in normal values, could play an important role in pathogenesis and stone formation, and also in cystinuria.

X-ray diffractometric analysis of L-cystine stones in 12 patients.

In 12 of 21 cystinuric patients, the components of cystine stones, either previously passed or removed at surgery, were studied by X-ray diffractometry and chemical analysis. The results of diffractometry suggested that, in addition to cystine, the stones contained sodium urate and ammonium magnesium orthophosphate hydrate, although chemical analysis was negative for these components. The role of uric acid in cystinuria is discussed.

Familial cystinuria in Ioannina District (Greece). Diagnosis and treatment.

The "Urocystin Test" has been used as a screening procedure for the diagnosis of the incidence of cystinuria in Ioannina District (Northwest Greece). From the 210 investigated urine samples, eight were positive and four of them were also L-cystine stone formers. All positive cases belong to two cystinuric families. The pedigree in village "Kato-Lapsista" is a genetic type of a "completely recessive cystinuria" while the other one in "Marmara" is the type of an "incompletely recessive cystinuria". All patients with L-cystine urolithiasis, except one child, were treated with the drug Thiola.

[Results of treatment of cystinuria and cystine lithiasis with alpha-mercaptopropionylglycine. Apropos of 40 patients]. / Résultats du traitement de la cystinurie et de la lithiase cystinique par l'alpha-mercaptopropionylglycine. A propos de 40 patients.

From 1987 to 1990, 719 subjects (385 males and 334 females) were screened, by means of urocystin-kit, for cystinuria and cystine lithiasis, in Epirus district (North-West Greece). The positive results were confirmed by chromatographic analysis of urine amino acids and laboratory tests. Forty patients, belonging to six cystinuric families, were identified. These patients were excreting 3.1 +/- 1.7 mmol/24 h of cystine in urine. All patients were treated by per os administration of alpha-MPG in daily doses of 400-1,200 mg/24 h). We therefore report the results of a 4 +/- 2 year follow-up of these patients. We conclude that treatment with alpha-MPG is very effective with minimal side effects in patients suffering from cystinuria or cystine urinary calculi.