Men10755 Nemorubicin

Nemorubicin (PNU-152243) (13) is a lipophilic analog of doxorubicin, where the amino group has been modified by a lipophilic and base-weakening 2-methoxymorpholide substituent. Both of these effects contribute to a higher lipophilicity than for doxorubicin, likely providing more rapid extravascular diffusion and cell uptake, and are considered to contribute to its observed lower cardiotoxicity. Nemorubicin acts as a prodrug, being converted in the liver, primarily by CYP3A, to a series of metabolites,71 one of which (PNU-159682) is considerably more potent than the parent compound, and is also active in in vivo tumor models.72 The potency and toxicity of nemorubicin can both be modulated by stimulators or inhibitors of CYP3A.71 It showed good in vitro activity against murine L1210 cells resistant to cis-platin73 and melphalan,74 and in vivo against P388 or LoVo cells and MX-1 mammary tumor xenografts,75

especially human hepatocellular carcinoma xenografts.76 In patients, nemorubicin was cleared rapidly from the circulation by extensive tissue distribution, with little renal excretion.77 In a Phase II trial as second-line therapy in soft-tissue sarcoma, using 1.23 mgm _ 2 every 4 weeks, nemorubicin gave 1/28 partial responses and 6/28 stable disease for at least 2 months, with no significant cardiotoxicity seen.78 It is currently in Phase II/III evaluation in hepatocellular carcinoma.72 Amrubicin

Amrubicin (14) is a totally synthetic anthracycline, and differs more substantially than nemorubicin from the parent doxorubicin. It lacks the 4-methoxy and 14-hydroxy groups on the chromophore and the 3'-amino group in the sugar unit, but has an amino group at the 9-position on the chromophore. It was designed as a less cardiotoxic anthracycline79 and is a prodrug, with the major metabolite (the 13-alcohol amrubicinol) being 3-8-fold more cytotoxic in cell culture than amrubicin itself.80 Both compounds act via topo II-generated double-strand DNA breaks.81 In human tumor xenografts the metabolite accumulates to higher levels than that of doxorubicin in the tumors but at lower levels in normal tissues, suggesting that its selective distribution plays a large part in the observed more potent therapeutic activity.82 Amrubicin was less active than doxorubicin against a panel of human lung tumor cell lines in culture,83 but was superior to doxorubicin in vivo in both murine tumor models and human tumor xenografts.84 In a series of human tumor xenografts in nude mice, there was a positive correlation between activity and the levels of the 13-alcohol metabolite in the tumors.85 Several Phase I trials, using different protocols, indicated maximum tolerated doses of 50-100 mg m _ 2, with leukocytopenia and thrombocytopenia as the major toxicities.86 A recent Phase I/II study of amrubicin and irinotecan in patients showed maximum tolerated doses of 45 mgm_2 and 100 mgm_2 respectively, with responses seen in about 10% of patients.87

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