Hematological toxicity associated with tiazofurin-influence on erythropoiesis.

In this study hematological toxicity was analyzed after the single and repeated applications of tiazofurin (TZF). Cellularity of bone marrow, spleen and peripheral blood was examined, spanning the period of fifty days after the initial application. Analysis of hematological parameters was performed by slightly modified conventional techniques. The fraction of erythroid series was monitored during the experiment. Presented data describe kinetics of damage and recovery of hemopoietic tissue. Our results indicate that the effect of tiazofurin on cellularity of bone marrow and spleen and on erythropoiesis is reversible and dose dependent within tested dose range and therapeutic regimes. Twenty days after the application normal function of hemopoietic tissues was restored. This approach and results can be useful in defining the timing for sequencing and combination therapy with tiazofurin.

Endogenous nucleosides in the guinea-pig eye: analysis of transport and metabolites.

This study investigates the transport of endogenous nucleosides and deoxynucleosides from the capillaries of the eye into the aqueous humour and the lens using the in situ vascular eye perfusion technique in the guinea-pig. The transport of [3H] adenosine and [3H] thymidine across the blood-aqueous barrier proved to be very rapid with a volume of distribution after 4 minutes perfusion reaching 11.9+/-3.0% and 9.93+/-1.1%, respectively. However, the transport of [3H] guanosine and [3H] cytidine was slower, with volumes of distribution reaching only 3.38+/-0.58% and 4.8+/-1.41%. The values for the entry of deoxyadenosine and deoxyguanosine were not significantly different from the values obtained for corresponding ribonucleosides (adenosine and guanosine) so that a change in the pentose sugar does not change the affinity of the nucleoside for the transport protein. Perfusion with a low sodium medium inhibited the transport of [3H] adenosine and [3H] thymidine into the aqueous humour. The presence of 800 nM NBTI also caused a decrease in adenosine transport into the aqueous humour, so that the volume of distribution after 2 minutes reached only 3.78+/-1.87%. These findings suggest that the transfer of adenosine across the blood-aqueous barrier has both concentrative and equilibrative components. The presence of 0.1 mM thymidine had no effect on the [3H] adenosine transport, whereas 0.1 mM of adenosine resulted in a marked decrease on the [3H] thymidine transport which suggests that the concentrative nucleotide transport is probably mediated by both cif and cit transport systems. The cellular uptake of nucleosides into the lens was very rapid and the volume of distribution of purine nucleosides was within the range of 30-50% whereas that for thymidine uptake was somewhat lower, reaching 20-30%. HPLC analysis of the eye structures in the guinea-pig showed that lens, vitreous body and the rest of the eye do not contain either free nucleosides or purine bases in detectable quantities, except for xanthine which was detected in aqueous humour at a concentration of 2.51+/-0.51 mM. However, serum of the anaesthetised guinea-pig did not contain xanthine in detectable amount so it seems that the metabolic degradation of the nucleosides in the guinea-pig eye progresses as far as xanthine, which is then accumulated in the aqueous humour.

Effects of a modified CMF treatment (cyclophosphamide, methotrexate and 5-fluorouracil) on hematopoietic tissues and Yoshida sarcoma in rats.

Effects of a modified CMF treatment on hematopoietic tissue and an implanted tumor were studied in rats. The modification of the treatment refers to the application of cyclophosphamide 24 h after methotrexate and 5-fluorouracil. The study was done on Wistar rats bearing Yoshida sarcoma in the ascites form. The controls were a) untreated animals bearing the tumor or b) treated conventionally with the 3 cytostatics and c) tumor-free animals under either conventional treatment or d) modified treatment. We examined survival, the appearance of metastases, and the regeneration of hematopoietic tissues. Improved survival, the absence of metastases, and improved regeneration of hematopoietic tissues was observed when modified CMF treatment was applied. These results support the importance of sequencing cytostatic protocols for basic hematological determinants and anti-tumor activity.

H-ras gene mutations in salivary gland pleomorphic adenomas.

The DNA from 17 specimens of pleomorphic adenoma of the salivary glands was screened for the presence of ras gene mutations, which are known to be involved in the pathogenesis of various human neoplasias. By a sensitive method of hybridization with synthetic oligonucleotide probes on in vitro amplified tumor DNA, point mutations, mainly in codon 12 of the H-ras gene, were detected in six tumor specimens (35%). This high incidence of mutated ras genes suggests that their alteration may play a role in the pathogenesis of pleomorphic adenomas.