2-2--bipyridyl-6-carbothioamide and Leukemia-P388

The cytotoxicity of hydroxyurea in combination with 2.2'-bipyridyl-6-carbothioamide (a potential inhibitor of ribonucleotide reductase) on P388 murine leukemia is reported. Synergistic activity was studied using various interpretations of the isobologram method and the combination index method. We evaluated the pros and cons of these methods and their overall usefulness. In our opinion, to obtain all possible information from a compound association, it is important to choose a formally correct method that (a) can quantitatively evaluate synergism or antagonism, (b) may offer the possibility of averaging final results, (c) needs a minimal amount of experimental data, and (d) is rapid. Moreover, we emphasize both the utility of testing at least three molar ratios of compound association and the importance of carefully choosing the fractional inhibition used in calculating the combination effect. Such evaluation of drug combinations gives information essential to the preparation of new anticancer drug regimens and to the early assessment of biochemical interactions.

Topics: 2,2'-Dipyridyl; Animals; Antineoplastic Agents; Chelating Agents; Data Interpretation, Statistical; Drug Screening Assays, Antitumor; Drug Synergism; Hydroxyurea; Leukemia P388; Mice; Ribonucleotide Reductases; Tumor Cells, Cultured

The mechanism of action of a synthetic compound--2,2'-bipyridyl-6-carbothioamide--was investigated by developing tumor lines resistant to it (P388-R1.5 and P388-R4). P388-R4 is resistant to inhibitors of ribonucleotide reductase (RR) while no resistance was observed to antitumor drugs having other targets (except to bleomycin). The resistance to inhibitors of the RR M2 subunit is higher than that to compounds active on the RR M1 subunit. Moreover, murine chromosome 12, in which the M2 structural gene was recently localized, was trisomic in the resistant lines. We conclude that it is possible to consider BPYTA a new inhibitor of the RR M2 subunit.

Topics: 2,2'-Dipyridyl; Animals; Antineoplastic Agents; Cell Cycle; Drug Resistance; Drug Screening Assays, Antitumor; Karyotyping; Leukemia P388; Mice; Ribonucleotide Reductases; Tumor Cells, Cultured

Compounds containing an N*-N*-S* tridentate ligand were synthesized and tested for antitumor activity against P-388 lymphocytic leukemia in mice. Of these, only 2,2'-bipyridyl-6-carbothioamide (1a) showed antitumor activity at relatively high dosage levels. Compound 1a was also evaluated against L-1210 and S180 cells in culture and found to have significant activity.

Topics: 2,2'-Dipyridyl; Animals; Antineoplastic Agents; Leukemia P388; Ligands; Mice; Mice, Inbred Strains; Pyridines; Structure-Activity Relationship