Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Lockhart, A. Craig; Bukowski, Ronald M.; Rothenberg, Mace L.; Wang, K. K.; Cooper, Wendy; Grover, J.K; Appleman, Leonard J.; Mayer, Peter; Shapiro, Mark; Zhu, Aijun

doi:10.1007/s00280-006-0362-y

Cited by 21 publications

(13 citation statements)

References 16 publications

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“…However, more evidence indicated that the regioselective hydroxylation was determined by the substituents at C3Ј (Frapolli et al, 2006;Gut et al, 2006). Many of the new-generation taxanes had modified substituents at C3Ј compared with paclitaxel, such as BAY59-8862 (Sano et al, 2006), IDN5390 (Ferlini et al, 2005), BMS-275183 (Broker et al, 2007), MAC-321 (Lockhart et al, 2007), and SB-T-1102 (Ojima et al, 1996). It would be helpful to synthesize metabolism-stable taxanes if we knew how substituents at C3Ј affected taxane's metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…To overcome these shortcomings, numerous novel taxanes superior to paclitaxel were synthesized (Ojima et al, 1996;Mastalerz et al, 2003;Barboni et al, 2005;Lockhart et al, 2007), and some of them such as BAY59-8862 (Sano et al, 2006), BMS-275183 (Broker et al, 2007), and MAC-321 (Lockhart et al, 2007) entered clinical trials. Many of these novel taxanes had modified substituents at C3Ј of the C13 side chain, where two phenyls were replaced by other functional groups (Sano et al, 2006;Broker et al, 2007;Lockhart et al, 2007). These structural modifications made the novel taxanes effective against paclitaxel-resistant tumor cells, more soluble, and/or more potent.…”

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confidence: 99%

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Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Jiangwei

Ge²,

Liu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:To investigate how taxane's substituents at C3 affect its metabolism, we compared the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3 position. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4؆ (M1) and C6␣ (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by 1 H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4؆-hydroxycephalomannine was generated predominantly by CYP3A4 and 6␣-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6␣ for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6␣ to C4؆, and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4؆-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4؆-hydroxylation, whereas paclitaxel adopted an orientation favoring 3-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V m . Our results demonstrate that relatively minor modification of taxane at C3 has major consequence on the metabolism.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Jiangwei

Ge²,

Liu³

et al. 2007

Drug Metab Dispos

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“…• Taxalog, a newly developed oral taxane, has demonstrated activity in taxane-resistant tumors including malignant mesothelioma. A Phase II study has recently been started in multiple centers for malignant mesothelioma based on promising Phase I results as well as preclinical data in mesothelioma cell lines [39]. • Vorinostat, a histone deacetylase inhibitor, is a novel class of therapeutic agents that inhibits deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Peritoneal Mesothelioma

Hesdorffer

Chabot

DeRosa

et al. 2008

Curr. Treat. Options in Oncol.

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Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.

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“…A Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumours showed that it can be safely administered orally once every 21 days up to a dose of 60 mg/m 2 [25] . There was substantial interpatient variability in the pharmacokinetic parameters; MAC-321 was rapidly absorbed with a mean C max value of less than 1 h and a median terminal phase elimination half-life of 45 h (range 20 -228 h).…”

Section: Milataxel (Mac-321)mentioning

confidence: 99%

New taxanes in development

Ferlini

Gallo

Scambia

2008

Expert Opinion on Investigational Drugs

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Background : Taxanes are presently widely employed for the medical treatment of cancer. However, despite the huge clinical success, these agents exhibit clinical problems related to poor drug solubility, toxicity and, in particular, drug resistance. Objective : To identify the critical points related to the process of development of novel taxanes. Methods : Publicly available data on the paclitaxel and docetaxel analogues, which have entered a clinical development phase in the last 2 years have been taken into consideration. The development involved novel formulations of paclitaxel and novel chemical entities. For each agent in each category the development phase is analysed and a synthetic comment for each category is included. Results/conclusions : Despite all the efforts, until now clinical success with the new development of taxanes has been limited. Moreover, the expected clinical introduction of epothilones could further restrict the space for development of novel taxanes. Despite these facts, some interesting concepts emerged during the process of development and could lead to successful drugs in the forthcoming years.

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Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Abstract: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was neutropenic fever. Four subjects had disease stabilization.

Cited by 21 publications

References 16 publications

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

Peritoneal Mesothelioma

New taxanes in development

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