Discriminative stimulus properties of the benzodiazepine receptor partial agonist beta-carbolines abecarnil and ZK 95962: a comparison with chlordiazepoxide

Separate groups of rats were trained to discriminate one of three benzodiazepine receptor ligands from vehicle. The three ligands used, the benzodiazepine chlordiazepoxide, and the beta-carboline partial agonists ZK 95962 and abecarnil, have been reported to have different agonistic profiles. All three ligands formed specific benzodiazepine-receptor mediated discriminative stimuli antagonizable by at least one benzodiazepine antagonist. Different patterns of generalization were observed for each cue. As reported previously full and partial agonists substituted for chlordiazepoxide, whereas generalization to ZK 95962 was obtained more readily with partial agonists and antagonists with weak partial agonist activity. In contrast to the other two cues, the abecarnil discriminative stimulus was difficult to train and was unstable over time. Additionally, the abecarnil cue showed commonalities only with sedative or BZ1 receptor agonists. These results demonstrate qualitative differences between different benzodiazepine receptor ligands dependent on the intrinsic activity of the compound used.     

Enhanced cell killing in lewis lung carcinoma and a human pancreatic-carcinoma xenograft by the combination of cytotoxic drugs and misonidazole.

The "chemosensitizing" properties of the radiosensitizer misonidazole (MISO) were examined in 2 tumour systems, murine Lewis lung carcinoma and human pancreatic adenocarcinoma xenografted into immune-suppressed mice, using a soft-agar colony assay to measure tumour-cell survival. In mice bearing Lewis lung tumour, the administration of MISO simultaneously with melphalan, cyclophosphamide. CCNU, FU or vincristine gave substantial enhancement of cytotoxicity (DEFs from 1.5 to 3.5). However, no enhancement was seen with bleomycin, VP 16-213 or cis-Pt. The same level of enhancement of cyclophosphamide effect (DEF = 2.0) was seen with both cell survival and growth delay end-points effect (DEF = 2.0) was seen with both cell survival and growth delay end-points of tumour response. Enhancement was also seen in the human tumour xenograft with melphalan, cyclophosphamide and MeCCNU, using a cell survival assay, but cis-Pt was again not enhanced.