Subject(s)
Blood Platelets/pathology , Platelet Glycoprotein GPIb-IX Complex/analysis , Platelet Glycoprotein GPIb-IX Complex/metabolism , Thrombocytopenia/blood , Animals , Antibodies, Monoclonal , Blood Platelets/chemistry , Humans , Immunoenzyme Techniques , Male , Mice , Platelet Count , Platelet Glycoprotein GPIb-IX Complex/immunology , Purpura, Thrombocytopenic, Idiopathic/blood , RabbitsABSTRACT
The authors studied the degree of DNA damage in in vitro cultured human peripheral lymphocytes (PL) and Jurcat's human T-cell lymphoma cells exposed to a stabilized 4 OH-cyclophosphan-mamophosphatide (MA) derivative, as well as in the leukocytes from patients with leukemia who were treated with cyclophosphan. There was an increase in alkaline DNA denaturation rate of LP lysates and T-cell lymphoma cells, which was in proportion to MA concentrations, and a higher sensitivity of LP to the genotoxic effect of MA given in doses of 5-10 micrograms/ml than that of Jurcat's cells, as well as high peripheral lymphocyte and neutrophil DNA damages in patients with leukemia during chemotherapy. The authors consider that the accumulation of single-strand breaks and alkaline-labile sites, which was recorded from the increase in alkaline DNA denaturation rate of cell lysates, is a highly sensitive test for detecting DNA damages in resting and slowly proliferating cells and can be useful in revealing and evaluating the severity of human genotoxic effects.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/pharmacology , DNA, Neoplasm/drug effects , Leukemia/blood , Leukocytes/drug effects , Antineoplastic Agents/therapeutic use , Cyclophosphamide/therapeutic use , DNA Damage , DNA, Neoplasm/blood , Female , Humans , Leukemia/drug therapy , Leukocytes/metabolism , Lymphoma, T-Cell/blood , Lymphoma, T-Cell/drug therapy , Male , Nucleic Acid Denaturation/drug effects , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolismABSTRACT
The data were obtained formerly that mice of certain strains essentially differ in the sensitivity to the immunodepressive and antiproliferative action of the alkylating agents (so-called opposite strains: DBA/2--highly sensitive, BALB/c--resistant). It is shown in the present work that with the use of the other non-alkylating immunodepressive agents (cytarabine, cyclosporin A, dexamethasone) that differ in the action mode, DBA/2 mice retain a high sensitivity whereas BALB/c mice a low sensitivity to all the immunodepressants. The sensitivity to the immunodepressive action in vivo directly correlates with that of the immunocompetent cells in vitro. Potential mechanisms determining the same type sensitivity to diverse immunodepressant in mice belonging to the above-indicated genotypes are under discussion.
Subject(s)
Immunosuppressive Agents/pharmacology , Pharmacogenetics , Alkylating Agents/pharmacology , Animals , Antibody-Producing Cells/drug effects , Cells, Cultured , Drug Resistance , Drug Tolerance , Genotype , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Spleen/cytology , Spleen/drug effects , T-Lymphocytes/drug effectsABSTRACT
Phynoptin (Ph) and cyclophosphamide (CP) gave rise to a type I spectral changes with liver microsomal fraction. KS were 15 microM and 2150 microM, respectively. Ph increases the concentration of NBP product(s) of CP and acrolein in the blood plasma of animals. Ph increases a toxicity of CP. LD50 was 388.0 +/- 13.9 mg/kg for CP and LD50 was 342.8 +/- 16.9 mg/kg for CP in combination with Ph. Ph changes a therapeutic action of CP in mice with hemocytoblastosis La. Pharmacokinetic interactions have been demonstrated between calcium antagonists Ph and CP.
Subject(s)
Cyclophosphamide/pharmacokinetics , Verapamil/pharmacology , Animals , Cyclophosphamide/pharmacology , Cyclophosphamide/therapeutic use , Dose-Response Relationship, Drug , Drug Interactions , Drug Screening Assays, Antitumor , In Vitro Techniques , Leukemia, Experimental/blood , Leukemia, Experimental/drug therapy , Leukemia, Experimental/mortality , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Neoplasm Transplantation , Verapamil/therapeutic useABSTRACT
It has been established in experiments in vitro that splenocytes of DBA/2GSto mice are more sensitive to the immunosuppressant action of the alkylating agents (cyclophosphamide, sarcolysine and thiophosphamide) than splenocytes of BALB/cGLacSto mice. Splenocytes of C3H/SnRap mice exhibit and intermediate type of sensitivity. T-lymphocytes of the spleen of BALB/cGLacSto and DBA/2GSto mice are more sensitive in vitro to the action of active metabolites of cyclophosphamide as compared to B-lymphocytes, with both types of the cells of DBA/2GSto mice being affected to a greater extent than the cells of BALB/cGLacSto mice.
Subject(s)
Alkylating Agents/pharmacology , B-Lymphocytes/drug effects , Mice, Inbred Strains/immunology , Spleen/drug effects , T-Lymphocytes/drug effects , Animals , B-Lymphocytes/immunology , Genotype , Immunosuppressive Agents/pharmacology , Mice , Species Specificity , Spleen/immunology , T-Lymphocytes/immunologyABSTRACT
Experiments were made on BALB/cJ YSto and WR/Y mice to study the immunosuppressant action of cyclophosphamide (CP) and thiophosphamide (thiotepa) in vivo. WR mice were found to be significantly more sensitive to the immunosuppressant action of thiotepa than BALB/c mice and to have similar sensitivity to the action of CP. BALB/c mice appeared highly resistant to the action of both the drugs. Based on the data obtained and those reported in the literature a possible parallelism is suggested between the mutagenic and immunosuppressant action of CP and thiotepa.
Subject(s)
Cyclophosphamide/immunology , Immunosuppressive Agents/immunology , Mice, Inbred BALB C/immunology , Mice, Inbred Strains/immunology , Thiotepa/immunology , Animals , Antibody-Producing Cells/drug effects , Dose-Response Relationship, Immunologic , Drug Resistance , Mice , Species SpecificityABSTRACT
A study was made of variability of the sensitivity of peripheral blood lymphocytes from different donors to an antiproliferative action of cyclophosphamide and thiophosphamide. A similar degree of the sensitivity was revealed to alkylating agents differing in the action mode, with this degree being independent of the "stimulation index" magnitude.
Subject(s)
Alkylating Agents/pharmacology , Lymphocytes/drug effects , Animals , Cell Division/drug effects , Cyclophosphamide/pharmacology , Female , Humans , Male , Mice , Mice, Inbred BALB C , Thiotepa/pharmacologyABSTRACT
The immunodepressant action of cyclophosphamide, thiophosphamide and sarcolysine was examined in experimental primary immune response in mice of different lines immunized with sheep red blood cells. DBA/2 and C3H/Sn mice were marked by the highest sensitivity to the immunodepressant action of the alkylating agents. BALB/c mice were relatively resistant to the immunodepressant action. Possible reasons for the interspecific differences found are discussed.
Subject(s)
Alkylating Agents/immunology , Immune Tolerance/drug effects , Mice, Inbred Strains/genetics , Animals , Antibody-Producing Cells/drug effects , Cyclophosphamide/immunology , Drug Resistance , Melphalan/immunology , Mice , Species Specificity , Thiotepa/immunologyABSTRACT
The paper is concerned with activation of cyclophosphamide by mouse liver microsomes in vitro. Liver microsomes from BALB/c mice metabolize cyclophosphamide more effectively as compared with those from DBA/2 mice, which manifested by a more intense output of products having alkylating or immunodepressant properties. This seems likely to be a consequence of the increased P-450 cytochrome content in liver microsomes from BALB/c mice, as well as of its structural characteristics in the mouse. The relationship between the immunodepressant effect of cyclophosphamide in vivo and in vitro in mice of varied genotypes is discussed.
Subject(s)
Cyclophosphamide/metabolism , Immunosuppressive Agents , Microsomes, Liver/metabolism , Animals , Biotransformation , Cyclophosphamide/pharmacology , Cytochrome P-450 Enzyme System/analysis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Inbred DBA , Microsomes, Liver/analysis , Species SpecificityABSTRACT
The alkylating and immunodepressive activity of the serum of CBA, BALB/c and DBA/2 mice was studied after the cyclophosphamide administration. The interstrain differences between the indices under study were revealed; no direct correlation was shown between them. DBA/2 mice were found to be the most sensitive to the immunodepressive action of cyclophosphamide, and had the highest blood serum immunodepressive activity.
Subject(s)
Cyclophosphamide/immunology , Immunosuppression Therapy , Alkylation , Animals , Cyclophosphamide/blood , Dose-Response Relationship, Immunologic , Immune Sera/genetics , Immune Sera/immunology , Immunogenetics , Male , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Inbred DBA , Time FactorsABSTRACT
A study was made of the immunodepressive effect of cyclophosphamide (CP) on mice of 3 strains (BALB/c, CBA, and DBA/2) immunized with sheep red blood cells (SRBC). With the optimal immunizing dose of the antigen (5 X 10(8) SRBC) the most pronounced immunodepression was noted in DBA/2 mice, and with the high dose (6.2 X 10(9))--in DBA/2 and CBA mice. The CP action proved to depend on the dose of the antigen administered; in BALB/c mice a reduction in the number of the antibody-forming cells was the same with both SRBC doses, in DBA/2 mice an increase of the antigen dose led to reduction of immunode pression, and in CBA mice -- to its enhancement (with sufficiently high CP doses). Determination of the rate of oxidative CP hydroxylation by the liver microsomes of mice showed it to be comparatively low in DBA/2 and CBA mice, and much greater in BALB/c mice. It is supposed that the detected differences in the immunodepressive action of CP could be connected with different sensitivity of the target cells and (or) with the peculiarities of its metabolism in mice belonging to different strains.
