Phase I trial with farnesyltransferase inhibitor R115777 in patients (pts) with advanced solid tumors

Punt, C.J.A.; Peters, Mary Linton B.; Maanen, L. van; Walle, Baudouin van de; Bol, C.J.; Willems, Lucas; Horak, Ivan D.; Palmer, Peter; Wagener, D.J.T.

doi:10.1016/s0959-8049(99)81588-3

Cited by 2 publications

(3 citation statements)

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“…Tipifarnib is the FTI most extensively studied in phase I clinical trials [49,55,217,[217][218][219][220][221][222][223]. From these studies, maximum tolerated doses of 300 to 1200 mg tipifarnib b.i.d.…”

Section: Tipifarnib (R115777)mentioning

confidence: 99%

“…were demonstrated [217]. Dose-limiting toxicities for this compound were found to be neutropenia, myelosuppression and neurotoxicity, frequently associated with fatigue and gastrointestinal toxicity, and in some cases with headache, neuropathy and anemia [55,217,218,223]. Pauses in therapy were found to lead to increased tolerability without compromising the clinical activity of this compound.…”

Section: Tipifarnib (R115777)mentioning

confidence: 99%

“…Pauses in therapy were found to lead to increased tolerability without compromising the clinical activity of this compound. [55,222,223].…”

Section: Tipifarnib (R115777)mentioning

confidence: 99%

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Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Sousa

Fernandes²,

Ramos³

2008

CMC

107

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Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzyme's active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.

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