The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo

Shu, Bin; Yaremko, Bohdan; Hajian, Gerald; Terracina, Gaby; Bishop, W. Robert; Liu, Ming; Nielsen, Loretta L.

doi:10.1007/s002800000170

Cited by 107 publications

(75 citation statements)

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“…This effect was independent of the sequence of exposure, and appeared to be related to synergistic induction of G2/M cell cycle arrest. These initial findings have been supported by recent preclinical studies with both R115777 and Sch-66336 in combination with paclitaxel (Ranganathan et al 1999, Skrazt et al 1999, Shi et al 2000. The recent finding that Sch-66336 prevents farnesylation of centromere binding proteins (Ashar et al 2000) raises the possibility of a direct FTI effect on microtubule formation during the G2/M phase of the cell cycle which, in turn, may lead to enhanced sensitivity to the microtubule stabilising action of the taxanes.…”

Section: Potential For Combined Therapy With Ftis In Breast Cancersupporting

confidence: 66%

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Johnston¹,

Kèlland²

2001

Endocrine-Related Cancer

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Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the Ras protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in ras-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors (FTIs) on cancer cells, it is clear that tumours without oncogenic ras mutations such as breast cancer may also be targets for FTI therapy. This article reviews the rationale for the development of FTIs, focussing on early preclinical data in breast cancer models together with preliminary results from the first phase II study of an FTI in advanced breast cancer.

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Section: Potential For Combined Therapy With Ftis In Breast Cancersupporting

confidence: 66%

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Johnston¹,

Kèlland²

2001

Endocrine-Related Cancer

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“…However, L-744,832 exhibited synergy with paclitaxel and epothilone B in several cancer cell lines, including MCF7 (Moasser et al -Related Cancer (2004) 11 191-205 www.endocrinology.org 1998). SCH 63366 and R115777 also appear to be synergistic with paclitaxel (Ranganathan et al 1999, Skrazt et al 1999, Shi et al 2000. SCH 63366 is synergistic with cisplatin in A 549 lung cancer cells, but the combination is not even additive in MCF7 cells (Adjei et al 2001).…”

Section: Ftis In Combination With Other Agentsmentioning

confidence: 99%

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

O’Regan¹,

Khuri²

2004

Endocr Relat Cancer

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The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.

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“…56 FTI activity in solid tumors is currently best achieved in combination, particularly with taxanes 57 and with radiation, 58 where there is substantial preclinical evidence for these combinations. [59][60][61][62][63] Other tumor types that may be particularly responsive include head and neck, glioma, and breast cancers. [46][47][48][49][50]55,64 Much effort is being devoted to optimizing the types of trials that will unmask the best ways in which to use this new class of drug.…”

Section: Attempts To Inhibit Ras Membrane Association-farnesyl Transfmentioning

confidence: 99%

Ras Family Signaling: Therapeutic Targeting

Cox¹,

Der²

2002

Cancer Biology & Therapy

188

131

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Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogenes in human cancers. Consequently, a considerable research effort has been made to define the function of Ras in normal and neoplastic cells and to target Ras for cancer treatment. Among the anti-Ras strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (farnesyltransferase inhibitors), (2) downstream signaling (Raf and MEK protein kinase inhibitors), (3) autocrine growth factor signaling (EGF receptor inhibitors), or (4) gene expression (H-ras and c-raf-1). Although a number of these inhibitors have demonstrated potent anti-tumor activities in preclinical models, phase I-III clinical trials have revealed unexpected complexities in Ras function and in the clinical development of target-based therapies. We review the current status of anti-Ras drug development, issues that have complicated their progression to the clinic, and possible future strategies for targeting Ras.

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The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo

Abstract: Clinical investigation of combination therapy using SCH66336 and taxanes in cancer patients is warranted. Further, SCH66336 may be useful for sensitizing paclitaxel-resistant tumors to taxane treatment.

Cited by 107 publications

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Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

Ras Family Signaling: Therapeutic Targeting

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