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Peripheral benzodiazepine receptor (PBZr) binding sites in isolated mitochondrial (m-fractions) and microsomal fractions (p-fractions) from androgen sensitive R-3327 Dunning G and H tumors were studied. Binding in both m- and p-fractions of these tumors was specific, saturable, and of high affinity. A very high density of PBZr was found in m-fraction from both types of tumors. In p-fractions the receptor density was 4- and 7-fold lower than m-fractions from G and H tumors respectively. Receptor densities in both m- and p-fractions from the poorly differentiated fast growing G turner was significantly higher than in the corresponding fractions from the well differentiated slow growing H tumor. These data suggest that in the androgen sensitive prostatic tumors the density of PBZr may be influenced by the growth rate and degree of differentiation.

The effects of carbachol and histamine on changes in cytosolic-free calcium ([Ca2+]i) and cell proliferation have been characterized in human ovarian cancer cells (OVCAR-3) and non-tumourigenic Chinese hamster ovary cells (CHO). The muscarinic agonist carbachol increased [Ca2+]i significantly with a rapid biphasic response due to both influx of extracellular calcium and release of calcium from intracellular stores. None of these effects were however seen in CHO cells. The increase in cellular calcium by carbachol was also confirmed by calcium uptake experiments using Ca-45. Carbachol increased Ca-45 uptake by 25% in OVCAR-3 cells but had no effect in CHO cells. Histamine also stimulated calcium mobilization in OVCAR-3 cells but had no effect in CHO cells. The response to histamine was also biphasic although the calcium increase was smaller than with carbachol. Data obtained with selective histamine antagonists showed that the response to histamine was mediated by H-1 histaminergic receptors. Both carbachol and histamine also stimulated cell growth of OVCAR-3 cells but were without effect on CHO cells. The cell proliferating effect of carbachol and of histamine on OVCAR-3 cells as well as the increase in [Ca2+], was totally blocked by atropine and selective H-1 histaminergic receptor antagonist pyrilamine, respectively. Fetal calf serum (FCS) which increased [Ca2+]i in both cell lines also caused a substantial increase in cell growth in the two cell lines. Verapamil partially and TMB-8 totally blocked carbachol stimulated release of calcium from intracellular stores, whereas prenylamine had only a minor inhibitory effect on calcium influx. The effect of verapamil and TMB-8 were most likely resulted from their inhibition of cholinergic receptors rather than a direct inhibition of intracellular calcium release. The carbachol induced effects on calcium transients were also partially inhibited by pertussis toxin and the phorbol ester PMA. Our data suggest that the mitogenic action of carbachol occurs through an increase in [Ca2+]i which promote DNA synthesis and cell growth. These data also indicate the involvement of both a pertussis toxin sensitive and insensitive G-protein as well as protein kinase C in the signal transduction pathway induced by carbachol.

The effect of administering divided dose schedules of TCNU was examined against the murine adenocarcinomas of the colon, MAC 13 and MAC 26, and the Lewis lung tumour and drug metabolism was examined in the different tumour bearing mouse strains. Bone marrow toxicity of the dose schedules was assessed using a spleen colony forming unit assay. In addition, the effect of drug scheduling was investigated in a Phase I clinical setting. Differing levels of efficacy of the divided dose schedules were observed in the different murine tumour models. A therapeutic advantage was found in the Lewis lung tumour whereas none was found in either MAC 13 or MAC 26 tumours. The extent and nature of TCNU metabolism varied between the mouse strains which might contribute to the differing activity-toxicity patterns obtained. The results suggest that divided dose scheduling of TCNU might only be useful in selected patients.