Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo

Total platinum contents and cisplatin-DNA adduct levels were determined in vivo in xenografted tumour tissues in mice and in vitro in cultured tumour cells of head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to cisplatin. In vivo, a panel of five HNSCC tumour lines grow ing as xenografts in nude mice was used. In vitro, the panel consisted of f ive HNSCC cell lines, of which four had an in vivo equivalent. Sensitivity to cisplatin varied three- to sevenfold among cell lines and tumours respec tively. However, the ranking of the sensitivities of the tumour lines (in v ivo), also after reinjection of the cultured tumour cells, did not coincide with that of the corresponding cell lines, which showed that cell culture systems are not representative for the in vivo situation. Both in vitro and in vivo, however, significant correlations were found between total platin um levels, measured by atomic absorption spectrophotometry (AAS), and tumou r response to cisplatin therapy at all time points tested. The levels of th e two major cisplatin-DNA adduct types were determined by a recently develo ped and improved P-32 post-labelling assay at various time points after cis platin treatment. Evidence is presented that the platinum-AG adduct, in whi ch platinum is bound to guanine and an adjacent adenine, may be the cytotox ic lesion because a significant correlation was found between the platinum- AG levels and the sensitivities in our panel of HNSCC, in vitro as well as in vivo. This correlation with the platinum-AG levels was established at 1 h (in vitro) and 3 h (in vivo) after the start of the cisplatin treatment, which emphasizes the importance of early sampling.