Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent

Abstract

A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has curative activity against the Colon 38 tumour in mice. Previous pharmacokinetic studies have demonstrated tumour-selective retention with approximately 20-fold higher area under the concentration-time curve (AUC) for tumour tissue as compared to normal tissues. We have investigated here whether such retention is tumour specific. Plasma and tissue pharmacokinetics were assessed in the murine Lewis lung (LL3) tumour in C57 BL/6 mice and in xenografts of the NZM4, NZM10 and NZM52 human melanoma lines in Balb/c Rag-1 immunodeficient mice. The in vitro cellular localisation of SN 28049 in murine and human cell lines was studied by confocal fluorescence microscopy. A 260-fold variation, from 8.9 μM h (NZM4) to 2,334 μM h (Colon 38), was found among the different tumours. Only small variations were observed in the corresponding plasma AUC (2.9-5 μM h). Moreover, in vivo activity, as measured by tumour growth delay, varied from 1 day (NZM4) to curative (Colon 38), consistent with the tumour pharmacokinetic data. In cultured cell lines, SN 28049 was found in cytoplasmic bodies, suggesting that drug sequestration could contribute to tumour pharmacokinetics. SN 28049 shows dramatic differences in both tumour AUC and antitumour activity against different tumours. These differences point to the presence of a tumour-specific uptake and retention mechanism.