[Hemopoietic precursor cells during the development of carminomycin resistance]. / Rodonachal'nye kletki gemopoéza pri razvitii rezistentnosti k karminomitsinu.

A comparative quantitative investigation of colony-forming ability of mouse bone marrow hemopoietic stem cells in the case of ordinary leukemia variant (P-388) and carminomycin-resistant variant (P-388/k) was carried out. Leukemia bearing mice received single injections of increasing doses of carminomycin on the 5th day after transplantation and 24 hours later the bone marrow was investigated for quantity of colony-forming units in the spleen (CFUs). Dynamics investigation of bone marrow cells in the case of P-388 and P-388/k (without treatment) reveals the common tendency to a decrease of these cells in the period before animal death. Sensitivity of colony forming cells (CFUs) to different doses of the antibiotic of mouse bone marrow in both cases (P-388 and P-388/k) was practically the same. Dynamics of CFUs in two populations of cells after a single injection of carminomycin in doses causing the killing of 50% of CFUs showed that the antibiotic inhibited CFUs equally (50%). However this inhibition in case of CFUs with P-388/k leukemia was almost five times longer than in the case of ordinary P-388 one. Based on the investigations conducted the second injection of the antibiotic to mice with P-388/k leukemia on the fifteenth day after the first one may be recommended.

[Cytological characteristics of carminomycin-resistant P-388 lymphoid leukosis]. / Tsitologicheskaia kharakteristika limfoleikoza P-388, rezistentnogo k karminomitsinu.

The carminomycin-resistant strain (P-388/c) of P-388 lymphoid leukemia is obtained. Resistance development is accompanied by higher sensitivity to cytostatics, rise of hyperploidy, replacement of the stem line, presence of definite markers in leukemic cells as well as by the appearance of a clone of cells with higher dry mass. At the level of CFUs after the carminomycin administration more remote terms of cell restoration than in case of P-388/c lymphoid leukemia are determined. The P-388/c lymphoid leukemia cells lost their sensitivity to carminomycin at the stage of the DNA synthesis. Accumulation of cells is observed in phase G2 of the mitotic cycle.

[Colony-forming ability of bone marrow hematopoietic cells in mice with transplanted leukemia during administration of carminomycin]. / Kolonieobrazuiushchaia sposobnost' gemopoéticheskikh kletok kostnogo mozga myshei s perevivnym leikozom pri vvedenii karminomitsina.

Effects of carminomycin on the colony-forming ability of bone marrow haemopoietic stem cells (CFUs) were compared in normal mice with steady state and actively regenerating bone marrow, and in P-388 and La leukemia-bearing mice. CFUs assays were performed 24 h after treatment of donor mice with the increasing doses of the drug. Leukemia-bearing mice received carminomycin on the 5th day after transplantation. The dose-effect curves were exponential for CFUS normal mice with both the steady state and active proliferation state of bone marrow. The maximal effect was found 24 h after injection of 0.7 mg/kg of carminomycin (ED50 for CFUS) being more pronounced in regenerating bone marrow. The dose-effect curves for leukemias were also exponential. In the case of La leukemia the killing of CFUs by carminomycin was the highest as compared with P-388 leukemia.

[Antileukemic activity of carminomycin complexes with a high-polymer DNA]. / Izuchenie protivoleikoznoi aktivnosti kompleksov karminomitsina s vysokopolimernoi DNK.

Complexes of carminomycin with DNA were prepared from lyophilized carminomycin and high polymer DNA of sturgeon milt. The complex formation was evident from a batochromic shift in the maxima at 450-600 nm and an increase in the absorption level at 545 nm. The carminomycin complexes with DNA had a relatively low general toxicity and higher antileukemic activity in studies on mice with tumor L-1210 as compared to the use of carminomycin alone. The maximum increase in the average life time of the animals was observed when a complex with a molar ratio of carminomycin and DNA of 1:10 (with respect to nucleotides) was used. It was found that the complex of carminomycin and DNA with a ratio of the components of 1:20 had a more pronounced effect on the animal hemopoiesis as compared to the use of carminomycin alone. It resulted in a more significant decrease in the number of the bone marrow myelokariocytes and peripheral blood erythrocytes and leukocytes.

[Comparative pathomorphological study of the experimental action of carminomycin and rubomycin on the heart]. / Sravnital'noe patomorfologicheskoe issledovanie deistviia na miokard karminomitsina i rubomitsina v éksperimente.

Comparative histological investigation of the toxic effect of carminomycin and rubomycin on the myocardium was carried out on mice BDF. It was found that the level of the morphological changes in the heart muscle depended on the antibiotic dose. The cardiotoxic effect of carminomycin was less pronounced than that of rubomycin.

[Action of carminomycin on leukemic cell proliferation and some problems of its use in the combined therapy of leukemias]. / Deistvie karminomitsina na proliferatsiiu leikoznykh kletok i nekotorye voprosy ego primenemiia pri kombinirovannoi terapii leikozov.

The effect of carminomycin on the mitotic cycle of the cells of the transplantable leukemia L-1210 and the therapeutic activity of other antitumor drugs, such as phopurine and cyclophosphane was studied on mice BDF1. It was found that the cells in phases S and G2 of the mitotic cycle were most sensitive to carminomycin. Transfer G1--S and phase G1 were characterized by resistance to the antibiotic effect. When carminomycin was used in combination with phopurine or cyclophosphane, clear dependence of the therapeutic efficacy on the treatment scheme was noted. Simultaneous administration of all the three drugs resulted in potentiation of the antileukemic effect. An analogous effect was observed when carminomycin was administered prior to phopurine or cyclophosphane. When the order of the drugs use was reverse, the efficacy of the combined therapy was significantly lower than the summation antileukemic effect of the drugs.

[Comparative experimental study of the antileukemia activity of carminomycin and rubomycin]. / Sravnitel'noe izuchenie v éksperimente protivoleikoznoi aktivnosti karminomitsina i rubomitsina.

The antileukemic activity of karminomycin and rubomycin was studied comparatively in parallel experiments with respect to 4 strains of transplantable leukemia, i.e. acute non-differentiated leukemia La, acute lymphoblast leukemia, L-1210 and P-388 and subacute lymphoblast leukemia No. 8 CRIHBT. The doses used were adequate by their toxicity. The tests of the therapeutic effectiveness were: an increase in the life time of the animals treated as compared to the control ones, a decrease in the leukocyte count and the number of the blast cells in the peripheral blood, a decrease in the leukemic infiltration of the organs and tissues of the animals treated. It was shown that karminomycin was more effective in the studied leukemia strains when it was used in the doses with equivalent toxicity. The more pronounced antileukemic activity of karminomycin was especially evident from histological examinations, which showed lower infiltration of the organs and tissues of the mice treated with karminomycin by the leukemic cells as compared to the animals treated with rubomycin.

[Action of carminomycin on the kinetics of cell proliferation and some problems of its combined use with other cytostatic agents]. / Deistvie karminomitsina na kinetiku kletochnoi proliferatsii i nekotorye voprosy kombinirovannogo primeneniia ego s drugimi tsitostaticheskimi agentami.

It was found autoradiographically that karminomycin in the therapeutic dose (0.7 mg/kg) significantly hindered cell proliferation of ascitic tumour L-1210, if the cells were at the stage of DNA proliferation during the drug administration. It was shown that karminomycin in a dose of 0.35 mg/kg administered intraperitoneally decreased the number of the leukemic cell of ascitic tumour P-388 by more than 2 times. Then the number of the leukemic cells increased and it doubled during 47 hours. Karminomycin in a dose of 0.7 mg/kg hindered leukemic cell proliferation during 120 hours. The effectiveness of karminomycin therapy in combination with phopurin or cyclophosphan depended on the treatment regimen. Potentiation of the antileukemic effect was noted in the simultaneus use of the drug or in the primary use of cerminomycin 2 hours before administration of phopurin or cyclophosphan. When phopurin or cyclophosphan was used 2 hours before administration of karminomycin, therapeutic effectiveness was lower.