Ivan Bartošek

Walker carcinoma 256: a model for studies on tumor-induced anorexia and cachexia.

Data on anorexia and cachexia induced by Walker carcinoma 256 in Sprague-Dawley rats were analyzed in order to standardize an experimental model using a statistical (nondeterministical) procedure for assessing the efficacy of potential orexigenic agents. This model was characterized by a mean survival time of 14 +/- 1 days and by food intake and body weight loss starting from day 6 after tumor implantation. The complex course of cachexia was characterized by reduction in the weight of gastrocnemius muscle and epididymal adipose tissue, taken as representative sites of loss of proteins and lipids.

l-Asparaginase effects on inhibition of protein synthesis and lowering of the glutamine content in cultured rat hepatocytes

Primary cultures of rat hepatocytes were exposed to various concentrations of L-asparaginase derived from Escherichia Coli. Protein synthesis was inhibited by about 33% and cellular glutamine was reduced proportionally to the enzyme concentration. However, protein synthesis was inhibited only by amounts of enzyme able to reduce glutamine to critical levels below 10 nmol/mg cell protein. These data suggest that the glutaminase activity which probably contaminates E. coli asparaginase may be responsible for reduced liver protein synthesis.

Comparative kinetics of benz(a)anthracene, chrysene and triphenylene in rats after oral administration: I. Study with single compounds

Distribution and elimination of benz(a)anthracene (B(a)A), chrysene (Ch), and triphenylene (Tr) were compared after oral administration of the single compounds to 7-8-week-old female rats. These four-ring isomers were chosen because of their different carcinogenicity. The compounds have high affinity for lipid-rich tissues such as brain, mammary and parametrial adipose tissue. The relative availability of these compounds in the tissues examined decreased in the order Tr greater than B(a)A greater than Ch, but fecal elimination diminished in the opposite order Ch greater than B(a)A greater than Tr. Availability and fecal elimination of single polycyclic aromatic hydrocarbons (PAH) were influenced by the dose and concentration of PAH in the vehicle.

Bone Invasion by Walker 256 Carcinoma, Line A in Young and Adult Rats: Effects of Etidronate

Line A of Walker 256 carcinoma implanted in the muscle adjacent to the tibia of young (6 weeks) and adult (9 months) male rats invaded the bone. Osteolysis and reactive growth were greater in the bone of young animals than in adults. Ethane-1-hydroxy-1, 1-bisphosphonate prevented bone lysis and tumor invasion of the cortex both in young and adult animals. This model may be useful for studies of age-related differences in tumor infiltration into the bone and for investigating drug effects on this process.

Comparative kinetics of oral benz(a)anthracene, chrysene and triphenylene in rats: Study with hydrocarbon mixtures

Distribution and elimination of benz(a)anthracene (B(a)A) was compared in blood, liver, brain, parametrial adipose and mammary tissue of young female rats after oral administration of the polycyclic aromatic hydrocarbons (PAH) singly or in equimolar mixtures with chrysene (Ch) or triphenylene (Tr). The relative availability of B(a)A in tissues was not influenced by Ch or Tr in the mixture. However, the presence of B(a)A halved the relative availability of Tr and raised that of Ch. The relative availability of the three isomers decreased in the order Tr greater than B(a)A greater than Ch; this may be correlated to their solubility in water.

Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma

SummaryThe plasma and tissue pharmacokinetics of fotemustine (diethyl-1-[3-(2-chlorethyl)-3-nitrosoureido]-ethylphosphonate) and BCNU (1,3-bis-[2-chlorethyl]-1-nitrosourea) were investigated in healthy control rats and in animals bearing either the nitrosourea-sensitive line A (W256/A) or the nitrosourea-resistant line B (W256/B) of Walker 256 carcinoma. The antitumor activities of these nitrosoureas were similar following i.v. doses ranging from 10 to 40 mg/kg. For both drugs, the survival of tumor-bearing rats was lower in the W256/B than in the sensitive W256/A line. Some sex differences were observed, female rats being more responsive than males to both drugs. Nitrosourea concentrations were assayed in plasma and tissues by differential pulse polarography so as to assess whether the pharmacokinetics could explain the differences in antitumor activity. The antineoplastic effects of fotemustine seemed to be influenced by its pharmacokinetics. The plasma AUC of the intact nitrosourea was higher in females than in males. Fotemustine was cleared 2–5 times more slowly than BCNU from tumor tissue, and its clearance was higher in W256/B- than in W256/A-bearing rats. This suggests that the antitumor activity in the responsive line might partly be due to longer exposure of the growing tumor to the drug. The distribution volume of both nitrosoureas in plasma was higher in tumor-bearing animals than in healthy controls, indicating that the tumor tissue probably constitutes an additional distribution space.

Pharmacokinetics of nitrosoureas: levels of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) in organs of normal and Walker 256/B carcinoma bearing rats after i.v. bolus.

The disappearance of 1,3-bis-(2-chlorethyl)-1-nitrosourea (BCNU) from plasma, liver, kidney, lung, brain, spleen, tumor tissue and epididymal adipose tissue of Walker 256/B carcinoma-bearing rats and healthy animals was measured by differential pulse polarography after i.v. bolus of the drug. Only BCNU, not its decomposition products, was detected by the Polarographic assay. Levels of BCNU in liver of tumor-bearing animals were significantly lower (about 10 times) than those on healthy rats. A bi-exponential fit was used to calculate the kinetics of BCNU in plasma, kidney, lung and brain, but no difference could be found between healthy and Walker tumor-bearing rats. BCNU disappeared faster from adipose tissue of tumor-bearing animals than from normals.

Polarographic assay of submicrogram quantities of cis-dichlorodiamineplatinum (II) in biological samples.

Differential pulse Polarographic assay of the antineoplastic agent cis-dichlorodiamineplatinum II and its analogues was performed after acid oxidative hydrolysis (HCIO4, HNO3, HCI) of biological samples (plasma, tissue homogenates, urine) and reaction with ethylenediamine. Platinum levels and kinetics were determined in blood and urine of patients with non-oat-cell lung carcinoma. Detection limit of the polarographic assay was 0.5 ng platinum; analytical error was ± 3%. Levels of free cis-dichlorodiamineplatinum (II) in plasma fell in samples stored at –20 °C; the half-life of free drug was 38 h.

Preservation of rat hepatic microsomal enzyme activities: Effect of low temperature and freeze-drying

About 30-70% of microsomal hydroxylation of aniline, 0-demethylation of 4-NO2-anisole, N-demethylation of aminopyrine, were lost when whole organs were frozen and kept at low temperatures (0 degrees, -20 degrees, -196 degrees C). When 9000 X g or 105000 X g fractions were prepared from fresh liver and subsequently frozen to different temperatures, there was little or no such loss of activity. The kinetics of the decrease in microsomal enzyme activities was followed during storage of frozen or freeze-dried microsomes at various temperatures. N-demethylation of aminopyrine appeared to be the most sensitive marker of microsome denaturation.

Microsomal enzyme activity in perfused rat liver

Abstract The activities of microsomal enzymes were observed during perfusion of livers isolated from both normal and phenobarbital treated rats. The hydroxylation of aniline and the O -demethylation of p -nitroanisol did not decrease substantially (by 10 per cent only) in the 9000 g fraction prepared from livers perfused for 4 hr. N -demethylation of aminopyrine was reduced by 60 per cent in the same experimental conditions. A similar decrease of N -demethylation was also observed when livers were isolated from animals treated with phenobarbital. The content of cytochrome P-450 in the microsomes was stable during a 4-hr perfusion of isolated liver. The decrease of N -demethylation of aminopyrine could be partly restored by the simultaneous infusion of nicotinic acid, which is a precursor of NAD and NADP biosynthesis.