Background:

Nemorubicin is a derivative of doxorubicin, and has antitumor activity.

Nemorubicin has antitumor activity, with IC70s of 578 ± 137 nM, 468 ± 45 nM, 193 ± 28 nM, 191 ± 19 nM, 68 ± 12 nM, and 131 ± 9 nM for HT-29, A2780, DU145, EM-2, Jurkat and CEM cell lines, respectively[1]. Nemorubicin acts through nucleotide excision repair (NER) system to exert its activity. Nemorubicin (0-0.3 μM) is more active in the L1210/DDP cells with intact NER than in the XPG-deficient L1210/0 cells. Cells resistant to nemorubicin show increased sensitivity to UV damage[3]. Nemorubicin is cytotoxic to 9L/3A4 cells, with an IC50 of 0.2 nM, 120-fold lower than that of P450-deficient 9L cells (IC50, 23.9 nM). Nemorubicin also potently inhibits Adeno-3A4 infected U251 cells with IC50 of 1.4 nM. P450 reductase overexpression enhances cytotoxicity of Nemorubicin[4].

Nemorubicin is converted to PNU-159682 by human liver cytochrome P450 (CYP) 3A4 in rat, mouse, and dog liver microsomes[2]. Nemorubicin (60 µg/kg) induces sifnificant tumor growth delay in scid mice bearing 9L/3A4 tumors, but shows no obvious effect on the tumor growth delay of 9L tumors in mice by i.v. or intratumoral injection (i.t.). Nemorubicin (40 µg/kg, i.p.) exhibits no antitumor activity and no host toxicity in mice bearing 9L/3A4 tumors[4].

[1]. Quintieri L, et al. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005 Feb 15;11(4):1608-17. [2]. Quintieri L, et al. In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes. Biochem Pharmacol. 2008 Sep 15;76(6):784-95. [3]. Sabatino MA, et al. Down-regulation of the nucleotide excision repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells. Mol Cancer. 2010 Sep 24;9:259. [4]. Lu H, et al. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404.