Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

Sparreboom, Alex; Kehrer, Diederik F.S.; Mathijssen, Ron H.J.; Xie, Ruiqin; Jonge, Maja J.A. de; Bruijn, Peter de; Planting, A. S. T.; Eskens, Ferry A.L.M.; Verheij, C D G W; Heus, Gerda de; Klaren, A; Zhang, S; Verhaeghe, Tom; Palmer, Peter; Verweij, Jaap

doi:10.1038/sj.bjc.6601732

Cited by 16 publications

(9 citation statements)

References 28 publications

(35 reference statements)

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“…All clinical studies included in this analysis contained an exclusion criterion in this line. 3,7,10,[21][22][23][24][25][26] Because of this skewed distribution, an alternative categorization of renal function, based on its mean and s.d., was chosen instead of conventionally used categorizations. Using the categorization according to the FDA, it was only possible to compare patients with a creatinine clearance over 80 ml/min to patients with a mildly impaired renal function (i.e., creatinine clearance between 50 and 80 ml/min), which resulted in comparable findings.…”

Section: Discussionmentioning

confidence: 99%

“…3,7,10,[21][22][23][24][25][26] Depending on the specific study protocol, patients with a serum creatinine levels on study-entry of <1.25 or 1.5 times the institutional upper limit of normal and/or a minimum creatinine clearance calculated according to Cockcroft-Gault of 60 ml/min were considered eligible. Common inclusion criteria for the various trials, which included pharmacokinetic analysis of irinotecan and its metabolites SN-38 and SN-38G, in which the participating patients have been described extensively elsewhere.…”

Section: Methodsmentioning

confidence: 99%

“…Common inclusion criteria for the various trials, which included pharmacokinetic analysis of irinotecan and its metabolites SN-38 and SN-38G, in which the participating patients have been described extensively elsewhere. 3,7,10,[21][22][23][24][25][26] Depending on the specific study protocol, patients with a serum creatinine levels on study-entry of <1.25 or 1.5 times the institutional upper limit of normal and/or a minimum creatinine clearance calculated according to Cockcroft-Gault of 60 ml/min were considered eligible. All trials were conducted according to the revised Declaration of Helsinki and were approved by the local medical ethical committee and written informed consent was obtained from all patients.…”

Section: Methodsmentioning

confidence: 99%

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Renal Function as a Predictor of Irinotecan-induced Neutropenia

Jong

Bol

Mathijssen

et al. 2008

Clin Pharmacol Ther

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Although approximately half of the administered dose of irinotecan is recovered in urine, scarce data are available on the association of renal function with irinotecan pharmacokinetics and toxicity. Here, these relationships are investigated in 187 patients treated with irinotecan in a three-weekly schedule. No significant effects on irinotecan pharmacokinetics were found in these patients. However, in 131 patients treated with the registered dose, categorized renal function was related to hematological toxicity. The incidence of grade 3-4 neutropenia decreased as function of creatinine clearance, particularly in nonsmoking patients (P < 0.01). Patients with slower creatinine clearance (35-66 ml/min) had a four-times higher risk of grade 3-4 neutropenia (58% vs. 14%; P < 0.001). This study suggests that pretreatment renal function values are associated with irinotecan-induced neutropenia. A confirmatory analysis is warranted to determine whether measures of renal function should be incorporated in future attempts toward individualized treatment with irinotecan.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Renal Function as a Predictor of Irinotecan-induced Neutropenia

Jong

Bol

Mathijssen

et al. 2008

Clin Pharmacol Ther

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“…Most of these clinical studies have been conducted in a phase I setting. Examples of drugs studied in combination with tipifarnib include gemcitabine [59,60,69,70], cisplatin [59,60], topotecan [233], irinotecan [234,235], docetaxel [236], paclitaxel [237], and doxorubicin-cyclophosphamide [43,238]. In addition to these promising phase I trials, the clinical activity of tipifarnib was already investigated in combination with gemcitabine in a phase III study involving a total of 688 patients with advanced pancreatic adenocarcinoma [42].…”

Section: Tipifarnib (R115777)mentioning

confidence: 99%

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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“…Phase I combinations with a number of agents have been reported, including the combination with irinotecan (204) and gemcitabine (205) and the triple combination with gemcitabine and cisplatin (206). These studies were designed to define the MTD of the combination, although some responses were noted.…”

Section: Clinical Activity Of Tipifarnib (R115777)mentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

Basso¹,

Kirschmeier²,

Bishop³

2006

Journal of Lipid Research

281

246

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Some proteins undergo posttranslational modification by the addition of an isoprenyl lipid (farnesyl-or geranylgeranyl-isoprenoid) to a cysteine residue proximal to the C terminus. Protein isoprenylation promotes membrane association and contributes to protein-protein interactions. Farnesylated proteins include small GTPases, tyrosine phosphatases, nuclear lamina, cochaperones, and centromereassociated proteins. Prenylation is required for the transforming activity of Ras. Because of the high frequency of Ras mutations in cancer, farnesyl transferase inhibitors (FTIs) were investigated as a means to antagonize Ras function. Evaluation of FTIs led to the finding that both K-and N-Ras are alternatively modified by geranylgeranyl prenyltransferase-1 in FTI-treated cells. Geranylgeranylated forms of Ras retain the ability to associate with the plasma membrane and activate substrates. Despite this, FTIs are effective at inhibiting the growth of human tumor cells in vitro, suggesting that activity is dependent on blocking the farnesylation of other proteins. FTIs also inhibit the in vivo growth of human tumor xenografts and sensitize these models to chemotherapeutics, most notably taxanes. Several FTIs have entered clinical trials for various cancer indications. In some clinical settings, primarily hematologic malignancies, FTIs have displayed evidence of single-agent activity. Clinical studies in progress are exploring the antitumor activity of FTIs as single agents and in combination. This review will summarize the basic biology of FTIs, their antitumor activity in preclinical models, and the current status of clinical studies with these agents.-Basso, A. D., P. Kirschmeier, and W. R. Bishop. Farnesyl transferase inhibitors. J. Lipid Res. 2006. 47: 15-31.

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Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

Cited by 16 publications

References 28 publications

Renal Function as a Predictor of Irinotecan-induced Neutropenia

Renal Function as a Predictor of Irinotecan-induced Neutropenia

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

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

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