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

Abstract

Summary 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 growing as xenografts in nude mice was used. In vitro, the panel consisted of five HNSCC cell lines, of which four had an in vivo equivalent. Sensitivity to cisplatin varied three-to sevenfold among cell lines and tumours respectively. However, the ranking of the sensitivities of the tumour lines (in vivo), 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 platinum levels, measured by atomic absorption spectrophotometry (AAS), and tumour response to cisplatin therapy at all time points tested. The levels of the two major cisplatin-DNA adduct types were determined by a recently developed and improved 32 P post-labelling assay at various time points after cisplatin treatment. Evidence is presented that the platinum-AG adduct, in which platinum is bound to guanine and an adjacent adenine, may be the cytotoxic 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.

A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia

“…In contrast to our study, Welters et al (40) found significant correlations between platinum-DNA adducts and tumor response in xenografted tumor tissues and in cultured tumor cells of head and neck squamous cell cancer. Other investigators have explored the relationship between platinum-DNA adduct formation in peripheral blood leukocytes and clinical response in patients undergoing chemotherapy.…”

Targeted Delivery of Cisplatin to Lung Cancer Using ScFvEGFR-Heparin-Cisplatin Nanoparticles

“…Whether the accumulation of Pt in the kidney relates to renal toxicity remains unknown; 27, 28 it has been reported that the Pt-DNA adduct but not the total tissue Pt levels could provide a more useful correlation with the renal damage induced by Pt. 29 …”

Cisplatin tumor concentrations after intra‐arterial cisplatin infusion or embolization in patients with oral cancer

“…This dose is about 2 times higher than the maximum intravenous dose that can be tolerated without STS protection and therefore probably yields higher dose intensity at the targeted tumor site, provided that the molar STS/CDDP ratio in the tumor remains low as compared with that in plasma. This precondition is particularly important during the first 30 to 60 minutes of the CDDP tumor exposure because cisplatin deoxyribonucleic acid adducts are mainly formed during this time 12 , 13 , 14 . Use of the IA cisplatin approach in more than 300 patients with squamous cell carcinoma of the oral cavity provided good clinical results with respect to response and toxicity 1 , 2 , 15 , 16 …”