mitoguazone and Leukemia-P388

Vesicles prepared from sucrose-palmitate-stearate and cholesterol encapsulating the anticancer drug methylglyoxal-bis-guanylhydrazone, were investigated. Treatment with drug-loaded vesicles of this composition in a q.d. 1-4 schedule resulted for murine leukemias P388 in nearly the same increase in life span as the corresponding dose of the free drug. Even very high dosages of sucrose-palmitase-stearate (up to 480 mg.kg-1.d-1) were tolerated by mice.

Topics: Animals; Capsules; Excipients; Female; Leukemia P388; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mitoguazone; Palmitates; Stearates; Sucrose

The influence of age of experimental animals on the antileukemic activity, toxicity and distribution of ambazone, a new potential antineoplastic agent, was studied in 2- and 12-month-old B6D2F1 mice. The predominant effect observed was a significant reduction of the antileukemic action of this compound in old-aged mice. Together with a slight increase in several toxicity parameters this caused a marked reduction of the therapeutic index in 12-month-old mice compared to younger individuals. Furthermore, a general tendency to increased ambazone levels in liver, kidneys and thymus of old-aged mice was observed. Our data therefore provide further evidence that age has to be taken into consideration as one factor that may account for the variety of drug response frequently observed during clinical therapy with anticancer agents.

Topics: Aging; Animals; Antineoplastic Agents; Carbon Radioisotopes; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Lethal Dose 50; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred Strains; Mitoguazone; Neoplasm Transplantation; Tissue Distribution

Dihydroambazone 1, a soluble derivative of ambazone, was tested with an admixture of ascorbic acid (0.1, 0.25, or 0.5% in distilled water) for antineoplastic activity by different routes (i.p., p.o., s.c., i.v.) against leukemia P388, and by s.c. application against Lewis lung carcinoma on B6D2F1-mice. The results were compared with that of ambazone. 1 was as active as ambazone upon the per os d 1-4 schedule only. Ascorbic acid, added for stabilization of 1, had no significant influence on the results. Intravenously given 1 was of low activity. It proved to be toxic at 100 mg/kg body mass. The i.v. toxicity was estimated approximately on B6D2F1-mice (LD50: 150 mg/kg; LD100: 175 mg/kg; maximum tolerated dose (MTD): 100 mg/kg. A comparison between the MTD's of 1 and ambazone in mice and rats (Wistar) showed partly a somewhat better p.o. compatibility of 1. The expectation of a favourable i.v. applicable derivative from the otherwise in water nearly insoluble ambazone could not be realized.

Topics: Animals; Antineoplastic Agents; Lethal Dose 50; Leukemia P388; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Mitoguazone; Rats; Rats, Inbred Strains

The aim of the present study was to investigate the influence of different stages of leukemia P388 on the pharmacokinetics of the antineoplastic agent mitoguazone in mice. It could be shown that, independent of the tumor stage investigated, the total clearance of mitoguazone is slightly reduced reflecting a moderate increase of AUC in the serum of leukemia-bearing animals. Furthermore, in an advanced tumor stage the drug levels in kidneys, liver, spleen and serum were found to be elevated to some extent in comparison to tumor-free controls in contrast to an earlier stage of leukemia. In conclusion, the tumor stage has to be considered as an important factor to which extent a neoplasia may alter the pharmacokinetics of drugs used for anticancer chemotherapy.

Topics: Animals; Body Weight; Female; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred Strains; Mitoguazone; Neoplasm Transplantation; Organ Size

The antineoplastic activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) against murine leukemia P388 was found to be markedly reduced in 12- and 18-month-old mice as compared to young animals. The immune response against sheep red blood cells (SRBC), a T cell-dependent antigen, was also strongly diminished in tumor-free old mice and was further suppressed after ambazone treatment. Since the antileukemic effect of ambazone disappeared more or less in congenitally athymic nude mice, in neonatally thymectomized or silica-pretreated animals, it has been concluded that the action of the compound seems to be limited to young adult immunocompetent tumor-bearing hosts. Therefore immunosenescence, primarily of T cell functions of old tumor-bearers, may represent a decisive factor influencing the antileukemic, especially curative effect of ambazone in aged animals. A combined treatment with ambazone and immunomodulators (thymalin or a splenopentin derivative) failed to improve the antileukemic effect in young and old leukemia P388-bearing mice.

Topics: Adjuvants, Immunologic; Aging; Animals; Antineoplastic Agents; Female; Immune System; Immunosuppression Therapy; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Mitoguazone; Peptide Fragments; Thymopoietins; Thymus Hormones; Tissue Extracts

The antitumor and antimetastatic effects of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, combined with an inhibitor of S-adenosylmethionine decarboxylase, either methylglyoxal bis(guanylhydrazone) (MGBG) or ethylglyoxal bis(guanylhydrazone) (EGBG), were studied in mice bearing P388 leukemia or Lewis lung carcinoma. Although EGBG is a more specific inhibitor of polyamine biosynthesis than the widely used MGBG, the antitumor effect of the DFMO-EGBG combination on P388 leukemia-bearing mice was less than that of the DFMO-MGBG combination. The prolongation of survival time by the DFMO(1000 mg/kg)-MGBG(25 mg/kg) combination was 2.65-fold, while that of the DFMO(1000 mg/kg)-EGBG(50 mg/kg) combination was 1.34-fold. When mice were fed a polyamine-deficient diet, stronger antitumor effects were exerted; the prolongation of survival time by the DFMO-MGBG and the DFMO-EGBG combinations was 2.89-fold and 2.03-fold, respectively. The antitumor effect of combined use of the two polyamine antimetabolites with mice on normal and polyamine-deficient diets correlated with a decrease of polyamine charge contents in the tumor cells. The above in vivo results were confirmed clearly in the KB cell culture system. The antimetastatic activity of DFMO on Lewis lung carcinoma-bearing mice was strengthened by the addition of MGBG or EGBG. The antimetastatic activity of the DFMO-MGBG or DFMO-EGBG combination did not parallel the polyamine charge contents in the primary tumor and blood.

Topics: Adenosylmethionine Decarboxylase; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboxy-Lyases; Eflornithine; Female; Leukemia P388; Leukemia, Experimental; Lung Neoplasms; Mice; Mitoguazone; Neoplasm Metastasis; Polyamines; Tumor Cells, Cultured

Mice and rats of various ages (3, 10-12, and 18-19 months) were inoculated with the transplantation tumours murine melanoma B16 (B16), mammary adenocarcinoma 755 (Ca-755), leukemia P388 (P388), and rat rhabdomyosarcoma RA-2 (RA-2). Subcutaneous (sc) growth of B16 was not markedly affected by the age of the syngeneic host whereas intravenously (iv) inoculated 12 months old C57BL/6 mice developed more pulmonary metastases than animals 3 months of age. Median survival time (MST) of 18 months old mice bearing Ca-755 was significantly shorter than that of younger individuals. In contrast, old rats that had been injected RA-2 iv survived longer than controls. Survival of DBA/2 mice inoculated intraperitoneally (ip) with P388 cells was not influenced by the age of the host. The antineoplastic activity of ambazone and, to a less extent, of 5-fluorouracil against P388 was drastically lower in 12 months old mice than in 3 months old tumour bearers. Likewise a graduate loss of antineoplastic activity of ambazone against Ca-755 was observed with increasing age of the mice, whereas the effect of ambazone and 5-fluorouracil against RA-2 did not depend on the age of the rats. It is suggested that tumour-host interactions as well as pharmacokinetics of a given drug may underlie age-related changes.

Topics: Adenocarcinoma; Aging; Animals; Antineoplastic Agents; Cell Division; Female; Fluorouracil; Leukemia P388; Leukemia, Experimental; Male; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mitoguazone; Neoplasm Metastasis; Rats; Rhabdomyosarcoma

There is some evidence in the literature that the pharmacokinetics of anticancer agents can be influenced by the presence of a tumor. Therefore several authors recommend pharmacokinetic studies of such drugs to be performed also in tumor-bearing animals (2, 5, 7). The aim of the present study was to evaluate the influence of different stages and routes of inoculation of leukemia P 388 in B6D2F1-hybrid mice on the tissue distribution of ambazone, a new potential antineoplastic drug. It could be emphasized that the drug levels in liver, kidneys and thymus were higher in advanced tumor-bearing than in control animals whereas in the spleen and in whole blood the opposite was true. The differences can be explained partially by changes in the erythrocyte binding of ambazone.

Topics: Animals; Antineoplastic Agents; Carbon Radioisotopes; Female; Kidney; Leukemia P388; Leukemia, Experimental; Liver; Male; Mice; Mitoguazone; Research Design; Spleen; Thymus Gland

Three spontaneous lymphomas of 23- to 24-month-old (AB/Jena X DBA/2 Jena)F1 females were serially transplanted into syngeneic hosts. They were histologically classified as malignant lymphoblastic lymphomas (ABDt2 and ABDt5) and as a malignant lymphoma of histiocytic type (ABDt6). All lymphomas disseminated into the liver, spleen, and pancreas, whereas ABDt2 and ABDt5 additionally infiltrated the bone marrow and leptomeninx. None of the tumors showed a leukemic growth form, but extreme granulocytosis was observed in leukemia P388-bearing mice. Since the lymphomas ABDt2 and ABDt5 expressed T-cell differentiation antigens Ly-1, Ly-2, and Ly-3, they are thought to be of T-cell origin. On the contrary to the lymphocytes of parental mouse strain ABDt2 and ABDt5 cells reacted with anti H-2.23 allosera. All tumors have been found to be sensitive to at least 5/7 clinically used anticancer drugs. But only ABDt2- and P388-bearing mice survived longer than 60 days after treatment with the potent anticancer drug 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone). Successful chemotherapy of both tumors was accompanied with resistance of the hosts against the second transplant of the same tumor. Summarizing the characteristics of the newly established transplantation tumors it is concluded that they can be recommended as screening models in the search for new antineoplastic agents.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Leukemia P388; Leukemia, Experimental; Lymphoma; Mice; Mitoguazone; Neoplasm Transplantation

The encapsulation efficiency and the leakage on storage of various types of liposomes prepared from different lipid compositions containing the anticancer drug methyl-GAG (methylglyoxal-bis-guanylhydrazone) were investigated. Treatment with methyl-GAG in a q.d. 1-4 schedule resulted in the murine leukemias P 388 and L 1210 (i.v.) in nearly the same increase in life span as the corresponding dose in liposomes. In a q.d. 1, 3 schedule methyl-GAG containing liposomes revealed comparable effects as the 4-day treatment with the free drug. The hypoglycemic effect of 80 mg/kg methyl-GAG, q.d. 1-4, could be normalized when the drug was administered in reverse-phase evaporation vesicles. We conclude that the liposomal encapsulation of methyl-GAG leads to a depot effect with a slight relief of toxicity.

Topics: Animals; Female; Hypoglycemia; Leukemia L1210; Leukemia P388; Liposomes; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mitoguazone; Neoplasms, Experimental; Time Factors

The synthesis of S-substituted derivatives of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone is described. The obtained 1,4-benzoquinone-guanylhydrazone-S-alkyl (resp. aralkyl)-isothiosemicarbazones, in comparison with the unsubstituted standard compound, showed a significantly decreased biological activity against the murine leukemias L 1210 and P 388 as well as against the growth of several kinds of bacteria. Therefore the S-substitution seems not to be useful for reaching a maximum activity.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Leukemia L1210; Leukemia P388; Mice; Microbial Sensitivity Tests; Mitoguazone; Structure-Activity Relationship

By means of four murine models, the authors demonstrated in vivo that 1,4-benzoquinone guanylhydrazone thiosemicarbazone (1), which is known to be antimicrobially active, and its hydrochloride (2) exert an antineoplastic effect. In leukaemia P 388 and leukaemia L 1210 both compounds had a curative action already after four oral administrations. The "cured" animals were resistant or cross-resistant to further transmissions of leukaemia. The resistance was transmissible by splenocytes.

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Drug Resistance; Guanidines; Kinetics; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred Strains; Mitoguazone; Neoplasms, Experimental; Rats