Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Cancer Chemother Pharmacol. 2013 Nov;72(5):1013-22. doi: 10.1007/s00280-013-2280-0. Epub 2013 Sep 14.
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.
多种抗癌药物，包括阿霉素和米托蒽醌，其结构中都含有与正电荷侧链相连的 DNA 嵌入发色团。这些药物通常通过使 DNA 拓扑异构酶 II 中毒来抑制肿瘤生长和存活。具有这些特性的苯并萘啶衍生物 SN 28049 对小鼠结肠 38 肿瘤具有治疗活性。先前的药代动力学研究表明，与正常组织相比，肿瘤组织具有约 20 倍更高的浓度-时间曲线下面积（AUC）的肿瘤选择性保留。我们在这里研究了这种保留是否具有肿瘤特异性。
在 C57BL/6 小鼠的 Lewis 肺（LL3）肿瘤和 Balb/c Rag-1 免疫缺陷小鼠的 NZM4、NZM10 和 NZM52 人黑色素瘤系异种移植瘤中评估了血浆和组织药代动力学。通过共聚焦荧光显微镜研究了 SN 28049 在小鼠和人细胞系中的细胞内定位。
不同肿瘤之间存在 260 倍的差异，从 8.9 μM h（NZM4）到 2334 μM h（结肠 38）。在相应的血浆 AUC（2.9-5 μM h）中观察到的变化很小。此外，如肿瘤生长延迟所测量的体内活性从 1 天（NZM4）到治愈（结肠 38）不等，与肿瘤药代动力学数据一致。在培养的细胞系中，SN 28049 存在于细胞质体中，这表明药物隔离可能有助于肿瘤药代动力学。
SN 28049 在不同肿瘤的肿瘤 AUC 和抗肿瘤活性方面均存在显着差异。这些差异表明存在肿瘤特异性摄取和保留机制。
