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Alex Sparreboom

Publications and source records attributed to Alex Sparreboom.

At least 19 recordsLinked to original sources
PubMed2007

Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias.

MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly x 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease.

Acetylation↗
PubMed2007

Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics.

A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.

Animals↗
PubMed2006

Pharmacogenetics of ABCG2 and adverse reactions to gefitinib.

Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non-small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug-induced diarrhea, with implications for optimizing treatment with such agents.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2006

Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia.

Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C>T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P=0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P=0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel.

PURPOSE: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. EXPERIMENTAL DESIGN: Women with metastatic breast cancer were treated with docetaxel (30 mg/m(2)) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. RESULTS: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m(2) [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m(2) (95% CI, 15.5-31.8) and 20.0 L/h/m(2) (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). CONCLUSIONS: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.

Adenocarcinoma↗
PubMed2006

Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel.

PURPOSE: Low-dose metronomic chemotherapy treatments, especially when combined with 'dedicated' antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL-free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem. EXPERIMENTAL DESIGN: The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts. RESULTS: ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol. CONCLUSIONS: Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.

Albumins↗
PubMed2006

Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values.

PURPOSE: The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. PATIENTS AND METHODS: Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average +/- 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. RESULTS: In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value < or = 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value > or = 2.05 m2. CONCLUSION Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (< or = 1.65 m2; 1.66 m2 to 2.04 m2; > or = 2.05 m2) are recommended.

Adult↗
PubMed2006

Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors. MATERIALS AND METHODS: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry. RESULTS: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n = 3), 800 mg bid (n = 3), 1600 mg bid (n = 6), 2200 mg bid (n = 5) and 3000 mg bid (n = 3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over three years. CONCLUSION: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.

2-Methoxyestradiol↗
PubMed2006

Determination of paclitaxel in human plasma following the administration of Genaxol or Genetaxyl by liquid chromatography/tandem mass spectrometry.

A sensitive and specific assay for paclitaxel in plasma has been developed to overcome limitations in previously published assays, using liquid chromatography with tandem mass spectrometric detection. Plasma samples (100 microL) were subjected to liquid-liquid extraction with 1-chlorobutane/acetonitrile (4:1, v/v), with [(2)H(5)]paclitaxel employed as the internal standard. Chromatography was carried out with a Waters SymmetryShield C8 column (50 x 2.1 mm, 3.5 microm). The total run time, including equilibration, was 8 min, using a gradient of acetonitrile and 10 mM ammonium formate, pH 4.0. The assay is accurate and precise over the range of 2-2500 ng/mL and has been successfully applied to study the clinical pharmacokinetics of two formulations of paclitaxel, Genaxol and Genetaxyl, given orally and intravenously.

Administration, Oral↗
PubMed2006

Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer.

AIMS: To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. PATIENTS AND METHODS: Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). RESULTS: Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. CONCLUSIONS: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.

Adult↗
PubMed2006

Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.

OBJECTIVE: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. METHODS: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism-based techniques. RESULTS: Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies. CONCLUSIONS: This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.

ATP-Binding Cassette Transporters↗
PubMed2006

Plasma protein binding of the investigational anticancer agent 2-methoxyestradiol.

2-Methoxyestradiol (2ME2) is an endogenously produced metabolite of estradiol currently being tested in phase I and II clinical trials as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of 2ME2. The distribution of 2ME2 in plasma was studied in vitro using plasma from healthy human volunteers and ex vivo using plasma from patients with cancer receiving the drug orally. The equilibrium dialysis method used to characterize plasma protein binding of 2ME2 utilized a tracer amount of [H]-2-methoxyestradiol on a 96-well microdialysis plate with a 5-kDa cutoff membrane and 250 mul of plasma. The time to equilibrium was approximately 24 h and the mean unbound fraction of 2ME2 (fu) over the observed concentration range in plasma of patients receiving 2ME2 orally was 0.019+/-0.0043. The mean fu was 0.027+/-0.0019 in plasma of healthy human volunteers. The binding was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. The binding was also unaffected by the presence of 2-methoxyestrone, one of the major metabolites of 2ME2. 2ME2 was found to bind in decreasing order to plasma>albumin>alpha1-acid glycoprotein>sex-hormone-binding globulin. Plasma concentration-time profiles of total 2ME2 and unbound 2ME2 concentrations in a patient with cancer receiving 2ME2 as a single oral dose were parallel to each other. Thus, indicating that plasma protein binding is not an important consideration in pharmacokinetic monitoring of 2ME2.

2-Methoxyestradiol↗
PubMed2006

Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention.

Several of the hormone-mediated cancers (breast, endometrial, ovarian, and prostate) represent major cancers in both incidence and mortality rates. The etiology of these cancers is in large part modulated by the hormones estrogen and testosterone. As advanced disease develops, the common treatment for these cancers is chemotherapy. Thus, genes that can alter tissue response to hormones and alter clinical response to chemotherapy are of major interest. The cytochrome P450 1B1 (CYP1B1) may be involved in disease progression and modulate the treatment in the above hormone-mediated cancers. This review will focus on the pharmacogenetics of CYP1B1 in relation to hormone-mediated cancers and provide an assessment of cancer risk based on CYP1B1 polymorphisms and expression. In addition, it will provide a summary of CYP1B1 gene regulation and expression in normal and neoplastic tissue.

Antineoplastic Agents, Hormonal↗
PubMed2006

The role of drug-metabolising enzymes in clinical responses to chemotherapy.

Interindividual differences in efficacy and toxicity of cancer chemotherapy are especially important given the narrow therapeutic index of these drugs. Pharmacokinetic and pharmacodynamic responses to chemotherapy are difficult to predict in a particular patient as numerous variables (e.g., age, gender, concomitant medications and concomitant illness) can alter drug responses. Inherited variations in genes involved in drug metabolism have also been shown to contribute to altered responses to cancer treatment. There are several clinically relevant examples of genetic polymorphisms in drug-metabolising enzymes that alter outcomes of patients treated with chemotherapy agents. It may be possible to predict a patient's response to a particular chemotherapy agent based on knowledge of their genetic composition through in vivo phenotyping of drug-metabolising enzymes.

Animals↗
PubMed2006

Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea. PATIENTS AND METHODS: Patients were treated with irinotecan in a multicenter, double-blind, randomized, placebo-controlled trial. Eligible patients received irinotecan (350 mg/m(2) once every 3 weeks) combined with neomycin (660 mg three times daily for three consecutive days, starting 2 days before chemotherapy) or combined with placebo. Blood samples were obtained for additional pharmacokinetic and pharmacogenetic analyses. RESULTS: Sixty-two patients were evaluable for the toxicity analysis. Baseline patient characteristics, systemic SN-38 exposure, and UGT1A1*28 genotype status (i.e., an additional TA repeat in the promoter region of uridine diphosphate-glucuronosyltransferase isoform 1A1) were similar in both arms. Although distribution, severity, and duration of delayed-type diarrhea did not differ significantly between arms, grade 3 diarrhea tended to be less frequent in the neomycin arm. The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2-3 diarrhea. In the neomycin arm, grade 2 nausea was significantly more common. CONCLUSION: Our results do not suggest a major role for neomycin as prophylaxis for irinotecan-induced delayed-type diarrhea. It is suggested that the UGT1A1*28 genotype status could be used as a screening tool for a priori prevention of irinotecan-induced delayed-type diarrhea.

Adult↗
PubMed2006

Clinical pharmacokinetics of docetaxel : recent developments.

Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network. The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products. Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent.

Animals↗