Men10755

MEN-10755 (15) is a des-4-methoxy derivative of doxorubicin, but with a disaccharide side chain; it was the first anthracycline disaccharide to be used clinically. The crystal structure of MEN-10755 bound to the oligodeoxynucleo-tide d(CGATGG)2 is broadly similar to other anthracycline-DNA complexes, except that two different binding sites exist; in one both sugar rings lie in the minor groove, while in the other the second sugar H-bonds to a guanine of a second DNA helix.88 MEN-10755 is a more potent topo II poison than doxorubicin (suggested due to replacement of the amino group on the first sugar), while having lower cardiotoxicity. The latter is possibly related to its slower rate of cell uptake, which leads to a higher cytoplasmic/nuclear ratio than for doxorubicin.89 In cumulative dose studies in rats comparing a range of anthracyclines, cardiotoxicity correlated with myocardial levels of the corresponding alcohol metabolites.90 Studies with human cardiac cytosol also showed that MEN-10755 had a lower rate of formation of the cardiotoxic alcohol metabolite than did doxorubicin, and that this alcohol has lesser ability to react at the active 4Fe-4S site of cytoplasmic aconitase.91 MEN-10755 is more effective than doxorubicin in human tumor xenografts in nude mice,92 but was not effective in cells expressing transport-mediated resistance.93 A Phase I trial of MEN-10755 established the maximum tolerated dose as 45 mgm_2, with the dose-limiting toxicity being neutropenia.94 No antitumor responses were seen in 25 patients. A second Phase I study92 recommended a 3-weekly regimen for Phase II.

7.05.3.2 Anthraquinones

These were developed in a search for intercalators with lower cardiotoxicity than doxorubicin, with the major early success being mitoxantrone (16).95 This compound, like the anthracyclines, binds tightly to DNA by intercalation, but the exact mode of this binding, and of the other anthraquinones (parallel or perpendicular to the base pair axis) has not been exactly established.

7.05.3.2.1 Pixantrone

Pixantrone (17) is an azaanthraquinone, evolved from mitoxantrone in a search for drugs with lower cardiotoxicity.96 It was selected from a series of analogs on the basis of high cytotoxic activity, significant in vivo antitumor efficacy (especially against lymphomas and leukemias) over a wide dose range, and a lack of delayed cardiotoxicity compared with other anthracenediones.97 It is a DNA intercalating agent and topo II inhibitor,98 but it is not clear if this is its only mechanism of action, since its DNA damaging effects do not correlate with cytotoxicity.99 While pixantrone is not as potent as mitoxantrone it is also less cardiotoxic at equieffective doses, less myelosuppressive, and shows better in vivo activity in leukemia and lymphoma models.96 The drug appears to be most useful in the treatment of non-Hodgkin's lymphoma100; a recent multicenter Phase II trial used a dose of 85 mg m _ 2 in a 3-weekly protocol, gave 9/33 remissions with a median relapse time of 17 + months, and recommended Phase III trials.101 Its low cardiotoxicity has led to proposals for its use instead of mitoxantrone in the long-term treatment of multiple sclerosis.102

0 0

Post a comment