Progress on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents

Zhang, Yingjie; Xu, Wenfang

doi:10.2174/1871520610808060698

Cited by 9 publications

(12 citation statements)

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“…This arrest results in a ring of condensed chromosomes circling unseparated spindle poles, commonly referred to as monoaster spindle with DNA in a rosette configuration (Tao et al, 2005). The essential role of KSP in cell cycle progression through mitosis in normal and tumor makes it a promising therapeutic target (Zhang and Xu, 2008).…”

mentioning

confidence: 99%

Kinesin spindle protein SiRNA slows tumor progression

Marra¹,

Palombo²,

Ciliberto³

et al. 2012

Journal Cellular Physiology

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The kinesin spindle protein (KSP), a member of the kinesin superfamily of microtubule-based motors, plays a critical role in mitosis as it mediates centrosome separation and bipolar spindle assembly and maintenance. Inhibition of KSP function leads to cell cycle arrest at mitosis with the formation of monoastral microtubule arrays, and ultimately, to cell death. Several KSP inhibitors are currently being studied in clinical trials and provide new opportunities for the development of novel anticancer therapeutics. RNA interference (RNAi) may represent a powerful strategy to interfere with key molecular pathways involved in cancer. In this study, we have established an efficient method for intratumoral delivery of siRNA. We evaluated short interfering RNA (siRNA) duplexes targeting luciferase as surrogate marker or KSP sequence. To examine the potential feasibility of RNAi therapy, the siRNA was transfected into pre-established lesions by means of intratumor electro-transfer of RNA therapeutics (IERT). This technology allowed cell permeation of the nucleic acids and to efficiently knock down gene expression, albeit transiently. The KSP-specific siRNA drastically reduced outgrowth of subcutaneous melanoma and ovarian cancer lesions. Our results show that intratumoral electro-transfer of siRNA is feasible and KSP-specific siRNA may provide a novel strategy for therapeutic intervention.

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confidence: 99%

Kinesin spindle protein SiRNA slows tumor progression

Marra¹,

Palombo²,

Ciliberto³

et al. 2012

Journal Cellular Physiology

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“…Inhibition of KSP forms monopolar mitotic spindles and arrests cells at mitosis, which leads to cell death [ 25 , 26 ]. KSP inhibitors have been shown to exhibit antitumor activity and are currently in clinical trials [ 7 , 9 ]. Because KSP localizes to mitotic microtubules, KSP inhibitors function exclusively during mitosis and are therefore selective to mitotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…In studies comparing ARRY-520 with some of the more clinically advanced compounds and standard of care agents, ARRY-520 was shown to have superior efficacy in multiple xenograft models [ 7 ] and is currently in a Phase I trial [ 8 ]. More importantly, since KSP is expressed predominantly in proliferating cells and is absent from post-mitotic neurons, KSP inhibitors do not induce peripheral neuropathy usually observed with traditional microtubule disrupting agents such as Paclitaxel [ 9 ]. The objective of this study is two-fold.…”

Section: Introductionmentioning

confidence: 99%

KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells

et al. 2009

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Background: We previously described a sub-population of epithelial ovarian cancer (EOC) cells with a functional TLR-4/MyD88/NF-κB pathway (Type I EOC cells), which confers the capacity to respond to Paclitaxel, a known TLR-4 ligand, by enhancing NF-κB activity and upregulating cytokine secretion -events that are known to promote tumor progression. It is therefore important to distinguish those patients that should not receive Paclitaxel; it is also important to identify alternative chemotherapy options that would benefit this sub-group of patients. The objective of this study is to determine if the KSP inhibitor, ARRY-520, can be a substitute for Paclitaxel in patients with Type I EOC.

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“…Eg5 is not expressed in non‐proliferating cells or in the adult peripheral nervous system, and so inhibition of Eg5 only targets actively mitotic cells [10]. Therefore, Eg5 inhibitors are not expected to cause the neurotoxic side effects commonly observed with traditional antimitotic agents [2,11]. Inhibition of Eg5 has been shown to cause cell death in a number of preclinical cancer cell lines and to have antiproliferative activity in human tumor xenograft models [11–15].…”

Section: Introductionmentioning

confidence: 99%

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

Esaki¹,

Seto²,

Ariyama³

et al. 2011

Archives of Drug Information

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IntroductionAZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors.MethodsIn this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0.ResultsOf the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients.ConclusionAZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

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Progress on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents

Cited by 9 publications

References 0 publications

Kinesin spindle protein SiRNA slows tumor progression

Kinesin spindle protein SiRNA slows tumor progression

KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

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