Monoclonal antibodies to the L1210 murine leukemia cell line and to a drug-altered subline.

A panel of murine monoclonal antibodies (MAbs) was produced by fusing NS-0 myeloma cells with spleen cells of a BALB/c X DBA/2 F1 mouse hyperimmunized against a highly immunogenic subline of the L1210 leukemia obtained by in vivo treatment of the L1210 parental line with the antitumor drug 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC). Among the 52 MAbs produced 16 (anti-D) were specifically cytotoxic in a complement-dependent cytotoxicity assay for the drug-altered subline and the others (anti-L) also cross-reacted with the L1210 parental leukemia. Six anti-D and three anti-L MAbs were selected for detailed studies of tissue specificity. In quantitative absorption experiments the antigens defined by these antibodies could not be detected on cells from normal mouse tissues (lung, liver, kidney, heart, spleen, and thymus). The reactivities of both anti-D and anti-L MAbs against a panel of L1210/DTIC sublines obtained at different times were assayed. The results showed that the antigenic specificities defined by anti-L MAbs were expressed on almost every L1210/DTIC subline while the anti-D MAbs detected antigenic structures specific for the L1210/DTIC used for the immunization. None of the MAbs tested cross-reacted with the L5178Y lymphoma or with its DTIC-altered sublines. The failure of anti-D MAbs to cross-react with cells from other L1210/DTIC sublines supports the hypothesis that the immunological alterations induced by the DTIC treatment are the consequence of mutagenic activity of the drug. On the other hand the presence of anti-L antigens on the cells of every L1210 subline indicates that the DTIC alteration is not accompanied by a loss of the tumor-associated antigen from the L1210 leukemia.

Reduction of 4-epiadriamycin cardiotoxicity by milrinone, a new cardiotonic agent.

Recently, several non-catecholamine, non-glycoside cardiotonic drugs have been described. New compounds include amrinone, sulmazole and milrinone. Milrinone, a close analogue of amrinone, is about 30 times more potent than amrinone. In attempts to alleviate anthracyclines toxicity, we have previously reported that amrinone and sulmazole reduced the negative inotropic effect of adriamycin and 4-epiadriamycin in isolated guinea pig atria. The present study reports the effects of 4-epiadriamycin on electrically driven isolated guinea pig left atrium, in normodynamic or hypodynamic conditions. Exposure for 60' to 4-epiadriamycin (100 micrograms/ml) caused a depression of contractile force and of maximal rate of contractile force (df/dt). The negative effects of 4-epiadriamycin are antagonized by milrinone at 20 micrograms/ml.

Antibacterial and cytotoxic effect of ceftazidime-mitoxantrone association.

Microbial infections are a major problem in tumor-bearing and in immunocompromised patients. In such conditions it is of paramount importance to know the possible interactions between anti-tumor and antimicrobial drugs. In the present work we investigated the relationship between Ceftazidime and Mitoxantrone. Ceftazidime and Mitoxantrone were tested alone and in combination for antibacterial activity against different strains of Gram- and Gram+ bacteria. The cytotoxic effect of combination Mitoxantrone-Ceftazidime was determined in cultured P388 leukemia cells. No interference with the antibacterial activity of Ceftazidime or with the cytotoxic activity of Mitoxantrone was observed.

The bactericidal effect on Pseudomonas strains of adriamycin associated with quinolones.

The in vitro antibacterial activity of quinolone compounds was assessed on strains of Pseudomonas aeruginosa isolated from clinical infections. The bactericidal effect of quinolones was high and their respective antibacterial properties with adriamycin remained unimpaired on strains both sensitive and resistant to betalactam and aminoglycoside antibiotics. The cytotoxic effect of the combination of adriamycin and quinolones was determined in cultured P388 leukemia cells: no interference with the cytotoxic activity of adriamycin was observed.

Bactericidal and cytotoxic effect of combination of norfloxacin and 5-fluorouracil.

Using the agar dilution technique, we examined the in vitro antibacterial activity of 5-fluorouracil and norfloxacin alone and in association against several bacterial strains. When administered in association, the two drugs did not antagonize each other in tests carried out on strains both sensitive and resistant to penicillins, cephalosporins, aminoglycosides, tetracyclines; furthermore their respective antibacterial properties remained largely unimpaired. The cytotoxic activity and the antitumoral effect of a combination of 5-fluorouracil and norfloxacin was determined in cultured tumor cells, and in mice bearing Ehrlich ascites carcinoma. No significant interference with the cytotoxic activity and antitumoral activity of 5-fluorouracil was observed.

Cytotoxic activity of a series of heteroaryl-ONN-azoxy-sulphones and aryl sulphonylhydrazones.

Synthesis of heteroaryl-ONN-azoxysulphones and pyrazolyl-ONN-azoxycyanides was carried out by the action of the appropriate reagents on the corresponding nitroso derivatives. Pyrazolyl-ONN-azoxyamides were obtained by hydrolysis of the corresponding cyanides. Synthesis of the arylsulphonylhydrazones was carried out by reacting R-substituted phenyl-sulphonylhydrazines on the isomers of methylfuroxancarbaldehyde. Cytotoxic activity was assessed on HeLa cells. Some of the compounds tested inhibit the colony-forming ability of the tumor cells at low concentrations.

Cytotoxic activity of aryl and heteroaroxylazoxy derivatives.

Synthesis of aryl and heteroarylazocyanides, azoxyesters and azoxysulphones, was carried out by the action of appropriate reagents on the corresponding nitroso derivatives and arylazoxyamides were obtained by hydrolysis of the corresponding azoxycyanides. Cytotoxic activity was assessed utilizing cultured P388 leukemia cells. Most of the compounds tested showed a marked cytotoxicity at concentrations below 1 micrograms/ml.

Potential antitumor agents XVII (1). Cytotoxic agents from indole derivatives and their intermediates.

New indole derivatives and their intermediates were tested as cytotoxic agents on a culture of P388 leukemia cells. The aldehyde 2a was more active than the thiosemicarbazones 3a, b and the nitrosourea 14. The chloroacetyl derivatives 10, 11 were the most potent cytotoxic agents.