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[Lysosomal hydrolase activity during development of experimental leukemia].

Activity of the lysosomal hydrolases DNAase II, acid RNAase and acid phosphatase was studied in the mouse liver and spleen under developing Friend's viral leukemia. The activity of DNAase II in the liver was considerably increased from the 12th day after inoculation of virus-containing material and reached the maximum by the 20th day of the experiment. The activity of acid phosphatase was changed insignificantly while that of acid RNAase showed no deviations from the control level. A possible role of the lysosomal hydrolases in leukemia development is discussed.

Acid Phosphatase↗

[Combination chemotherapy of experimental leukemia].

In the present work an attempt was made to gain greater therapeutic effect of diazane coupled with adriamycin and sarcolysin. Leucemias L-1210 and La served as a model. In leucosis La diazane was injected once in 5 days. Either an additional injection of adriamycin two days prior to diazane injection or sarcolysin injected simultaneously with diazane enabled the authors to obtain a distinct synergestic effect. In leucemia L-1210 a simultaneous administration of diazane and sarcolysin also contributes to considerably longer survival of leucemic animals. Such combinations are likely to be promising in their clinical use.

Animals↗

[Possible role of DNAse I in the development of experimental leukemia].

An increase in the DNAase 1 activity in the serum and an increase in the DNAase inhibitor activity in the spleen in the development of virus Friend leukemia were demonstrated. Increased activity of the inhibitor in the spleen was also revealed after intravenous injection of exogenous DNAase 1 into mice. A potential role of serum DNAase 1 in the development of experimental leukemia is discussed.

Animals↗

[Chromosome aberrations and genes in human and experimental leukemias].

Although determination of chromosomal abnormalities may be of limited usefulness for the diagnosis of leukemia, the recent advances in the molecular mechanism associated with chromosome aberration has been rapid. Chromosome translocation in Burkitt lymphoma and chronic myeloid leukemia was the most striking evidence for the oncogene activation. Other specific chromosome abnormalities for FAB-classified leukemias are also known. Translocated type of chromosome abnormalities between immunoglobulin or T-cell receptor genes and oncogenes may also affect the T and B-cell leukemogenesis. However, the role of trisomies found in human and experimental leukemias and the gene dosages had been thought to be most important until 1982, has not been unclear. Many types of phenotypically heterogeneous leukemias have been reported. t(4 ; 11) acute leukemia is one such leukemia which shows early B-cell and myelomonocytic nature. Heterogeneous leukemias have been called biphenotypic, hybrid and acute mixed leukemias. The terminology must be used the unified. Recent trials to use paraffin-fixed tissues and bone marrow smear for molecular analysis has been successfully reported. Basic analysis on the DNA degradation mechanism revealed the enzymatic activity might play an important role before the complete fixation.

Animals↗

Oxidation of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide to the corresponding 6-sulfonamide facilitates changes in biologic characterization that include activity against thiopurine-refractory experimental leukemia.

Preclinical investigations in vivo revealed unexpected differences in the biological characteristics of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide (sulfenosine, 1) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfonamide (sulfonosine, 2), two novel but structurally related derivatives of 6-thioguanosine (6TGR). Strikingly, the addition of a fully oxidized sulfur atom at the 6 position of sulfenosine produced a purine derivative (sulfonosine) that was remarkably active against experimental leukemia resistant to treatment with either sulfenosine or 6TGR. This slight structural modification also appeared to influence solubility, scheduling capability, and oral activity as well as penetration of the central nervous system (CNS) and the onset of cellular resistance. These findings underscore the dramatic changes in biologic activity that can be produced by subtle modifications in molecular structure. We trust they may also contribute to the development of improved clinical therapy.

Animals↗

Synthesis and biologic evaluation of the dopamine analog N-acetyldopamine in experimental leukemia in mice.

N-Acetyldopamine is a relatively nontoxic analog of dopamine that has shown significant antitumor activity in experimental L1210 and P388 leukemias. A convenient two-step chemical synthesis of this derivative provided a sufficient quantity of material to study the effects of the administration of this drug by a more frequent schedule. The antitumor activity in the L1210 and P388 systems was significantly improved when N-acetyldopamine was administered to (C57BL/6J x DBA/2)F1 (B6D2F1) mice three times daily for 4 days. Long-term survivors appeared, which indicated tumor kills in excess of 10(5) cells. The effects of dopamine and N-acetyldopamine on the incorporation of radioactively labeled thymidine (dThd) by proliferating tissues (tumor, bone marrow, and gastrointestinal mucosa) were examined in tumor-bearing B6D2F1 mice. The dThd incorporation into tumor cells was selectively inhibited in both the L1210 and P388 leukemias with less inhibition of bone marrow and gastrointestinal mucosa cells. One hour after a dose of 400 mg N-acetyldopamine/kg, dThd incorporation was completely suppressed by both P388 and L1210 tumor cells with minimal effects on bone marrow or gastrointestinal mucosa cells. The synthetic method reported here is applicable to the preparation of various derivatives for study.

Animals↗

Levodopa and dopamine analogs: dihydroxy and trihydroxybenzylamines as novel quinol antitumor agents in experimental leukemia in vivo.

Levodopa and dopamine demonstrate significant antitumor activity in several experimental systems. We have prepared the nonneurotoxic dihydroxybenzylamine (DHBA) analogs 2,3-DHBA, 3,4-DHBA, and 2,5-DHBA and the trihydroxy derivatives 2,3,4- and 3,4,5-trihydroxybenzylamine. These analogs demonstrated significant and reproducible antitumor activity in the ip P388 and L1210 lymphocytic leukemias. This activity was markedly increased when the drugs were given by multiple injections three times daily for 4 days. 3,4-DHBA and 2,3-DHBA resulted in 30% and 20% long-term survivors, respectively. There was a selective inhibition of thymidine incorporation and a relatively lesser effect on uridine and leucine incorporations. Inhibitory concentrations were between 0.1 and 1.0 mM. The trihydroxy derivatives were more potent, with inhibitory concentrations between 0.01 and 1.0 mM. Furthermore, the trihydroxy derivatives were also able to inhibit the incorporation of uridine and leucine as well as thymidine. The para derivative, 2,5-DHBA, although a potent inhibitor in vitro, was completely inactive in vivo. When L1210 and P388 tumor-bearing animals were given radioactive labeled thymidine in vivo following the administration of drugs. a selective inhibition of thymidine incorporation by tumor cells was observed, with essentially no effect on gut or bone marrow. Doses greater than 200 mg/kg completely suppressed the incorporation of radioactively labeled thymidine by tumor cells 1 hour after administration of drug. A similar dose response was observed in the more slowly growing P388 leukemia, suggesting that the antitumor effect did not strongly correlate with rate of the tumor. Since levodopa and dopamine are currently being evaluated in patients with metastatic melanoma, the availability of analogs with enhanced antitumor activity and broader antitumor spectrum are of interest.

Animals↗

[Relationship between the development of experimental leukemia and animals' capacity for a humoral immune response].

The tests on AKR and C57BL mice of different age were conducted using experimental models of transplanted Gross leukemia (the first passage), Pujman leukemia and spontaneous AKR mouse leukemia. An inverse relationship between the ability of mice to produce humoral antibodies and their susceptibility to transplantation of singeneic leukemic cells and the incidence of spontaneous leukemia has been established. The differences in the ability of the animals to develop immune response to a heterologous antigen were connected with the physiological processes of the aging organism. The data obtained indicated that the failure of one of the links of immunity did not always result in a higher risk of tumor development.

Animals↗

[Content of squalene and sterols in tissues of the hemopoietic system in normal rats and in experimental leukemia].

Contents of scvalene, sterols and their derivatives were studied in lymphoid tissues as well as in liver and kidney tissues of normal rats and the animals with Shvetz experimental leukosis. Amount of cholesterol and of its precursor scvalene was distinctly decreased simultaneously with an increase in total content of nonsaponified substances in thymus, spleen, bone marrow and liver tissue of rats with experimental leukosis. Scvalene was increased in kidney tissue. Simultaneous accumulation of hydroxycholesterol derivatives, among which 7-beta-hydroxycholesterol was identified, was observed in these tissues under conditions of leukosis. Role of cholesterol hydroxyderivatives in biosynthesis of sterols is discussed.

Animals↗

[Alterations in composition of sterols and in properties of erythrocyte membranes in rats with Shvetz experimental leukemia and after UV irradiation].

Amount of cholesterol was distinctly decreased but content of scvalene, lanosterol, 7-dehydrocholesterol and 7-beta-hydroxycholesterol--increased in erythrocyte membranes of rats with Shvetz experimental leukosis. At the same time, osmotic stability of erythrocytes and a pattern of acidic erythrogramms were altered. After UV irradiation of rats amount of cholesterol was increased as well as other unidentified substances appeared in erythrocyte membranes. These alterations appear to be one of factors responsible for development of body resistance to leukosis.

Animals↗