Telomeres and Telomerase. Ciba Foundation Symposium 211

1999 Cancer Research Campaig

Increase in type A virus particles induced in BALB/c mouse epidermis during chemical carcinogenesis.

Electron microscopic observations of normal BALB/c mouse epidermis revealed the presence of isolated intracisternal A particles. Hyperplasia, papilloma and carcinoma formation induced by topical application of the carcinogenic polycyclic hydrocarbons benz(a)pyrene (B(a)P) and 3-methylcholanthrene (MC) is accompanied by an increase in the mumber of A particles. Topical application of a non-carcinogenic irritant alpha-pinene (alpha P) failed to provide comparable changes. Examination of the nuclei indicated occasional electron dense granules in the nucleoplasm which became more common throughout the progression of carcinogenesis

C-type and intracisternal A-type virus particles during epidermal carcinogenesis by tobacco smoke condensate in BALB/c mice.

Electron microscopic observations of sequential stages of skin carcinogenesis induced by tobacco smoke condensate (SC) and a cyclohexane fraction of tobacco smoke condensate (G) revealed an increase in incidence of intracisternal A particles within the epidermal cells. Tumours induced by SC also contained C-type particles, but these were not seen in G-induced tumours or after irritant or solvent treatment. There was no evidence of an increase in intracisternal A particles after irritant or solvent treatment. A direct relationship between the proliferation of A particles and neoplastic growth of BALB/c mouse epidermis appears likely. The data suggest possible activation of a latent C-type virus by SC

The relationship between tissue levels of flavone acetic acid (NSC 347512) and site dependent anti-tumour activity in murine colon tumours.

Flavone acetic acid (FAA) is extremely active against subcutaneous transplantable tumours in mice, but disappointingly there has been no demonstrable clinical activity. Previous studies have shown that lung tumour deposits are less responsive than the same cells implanted subcutaneously. The aim of this study is to examine the tissue disposition of FAA in an attempt to explain this site-dependent activity. The data show clearly that FAA clearance curves are influenced by the presence of MAC 15A tumours growing either subcutaneously or systemically. The decreased clearance of FAA from MAC 15A tumour bearing animals does not however explain the resistance of lung deposits. Neither can this be explained by differences in metabolism in these different sites. Cytotoxic metabolites have not been detected either in vitro or in vivo and their role in the mechanism of action of FAA is questionable

Pre-clinical evaluation of a novel chloroethylating agent, Clomesone.

The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas