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Biomedical subjects

Michael Pollak

Publications and source records attributed to Michael Pollak.

At least 37 records · Page 2Linked to original sources
PubMed2004

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

Administration, Oral↗
PubMed2004

Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women.

Experimental evidence suggests that insulin and insulin-related growth factors may play a role in breast pathology through their mitogenic and anti-apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin-like growth factor-I (IGF-I), its major binding protein (IGFBP-3), the ratio IGF-I:IGFBP-3, c-peptide (a marker of insulin secretion) and the ratio c-peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, MI between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF-I, IGFBP-3 and the ratio IGF-I:IGFBP-3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c-peptide or of c-peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [CI] 1.4-6.5) and 3.3 (95% CI 1.5-7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% CI 0.7-3.0) and 1.6 (95% CI 0.8-3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women.

Adult↗
PubMed2004

Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells.

The clinical usefulness of trastuzumab (Herceptin; Genentech, San Francisco, CA) in breast cancer treatment is limited by the rapid development of resistance. We previously reported that IGF-I signaling confers resistance to the growth-inhibitory actions of trastuzumab in a model system, but the underlying molecular mechanism remains unknown. We used SKBR3/neo cells (expressing few IGF-I receptors) and SKBR3/IGF-IR cells (overexpressing IGF-I receptor) as our experimental model. IGF-I antagonized the trastuzumab-induced increase in the level of the Cdk inhibitor p27(Kip1). This resulted in decreased association of p27(Kip1) with Cdk2, restoration of Cdk2 activity and attenuation of cell-cycle arrest in G(1) phase, all of which had been induced by trastuzumab treatment in SKBR3/IGF-IR cells. We also found that the decrease in p27(Kip1) induced by IGF-I was accompanied by an increase in expression of Skp2, which is a ubiquitin ligase for p27(Kip1), and by increased Skp2 association with p27(Kip1). A specific proteasome inhibitor (LLnL) completely blocked the ability of IGF-I to reduce the p27(Kip1) protein level, while IGF-I increased p27(Kip1) ubiquitination. This suggests that the action of IGF-I in conferring resistance to trastuzumab involves targeting of p27(Kip1) to the ubiquitin/proteasome degradation machinery. Finally, specific inhibitors of MAPK and PI3K suggest that the IGF-I-mediated reduction in p27(Kip1) protein level by increased degradation predominantly involves the PI3K pathway. Our results provide an example of resistance to an antineoplastic therapy that targets one tyrosine kinase receptor by increased signal transduction through an alternative pathway in a complex regulatory network.

Antibodies, Monoclonal↗
PubMed2004

Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells.

Overexpression of the ErbB2 receptor in one-third of human breast cancers contributes to the transformation of epithelial cells and predicts poor prognosis for breast cancer patients. We report that the overexpression of ErbB2 inhibits IGF-I-induced MAPK signaling. IGF-I-induced MAPK phosphorylation and MAPK kinase activity are reduced in ErbB2 overexpressing MCF-7/HER2-18 cells relative to control MCF-7/neo cells. In SKBR3/IGF-IR cells, reduction of ErbB2 by antisense methodology restores the IGF-I-induced MAPK activation. The inhibition of IGF-I-induced MAP kinase activation in ErbB2 overexpressing breast cancer cells is correlated with decreased IGF-I-induced Shc tyrosine-phosphorylation, leading to a decreased association of Grb2 with Shc and decreased Raf phosphorylation. However, IGF-I-induced tyrosine-phosphorylation of IGF-I receptor and IRS-I and AKT phosphorylation were unaffected by ErbB2 overexpression. Consistent with these results, we observed that the proportion of IGF-I-stimulated proliferation blocked by the MAPK inhibitor PD98059 fell from 82.6% in MCF-7/neo cells to 41.2% in MCF-7/HER2-18 cells. These data provide evidence for interplay between the IGF-IR and ErbB2 signaling pathways. They are consistent with the view that the IGF-IR mediated attenuation of trastuzumab-induced growth inhibition we recently described is dependent on IGF-I-induced PI3K signaling rather than IGF-I-induced MAPK signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers.

To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50-69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37-1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38-1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50-1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.

Aged↗
PubMed2004

A polymorphic locus in the promoter region of the IGFBP3 gene is related to mammographic breast density.

BACKGROUND: Mammographic breast density is a significant risk factor for breast cancer. Women with dense tissue accounting for more than 60-75% of the area of the breast have a 4- to 6-fold increase in their risk of breast cancer, compared to women with little or no breast density. A high circulating level of insulin-like growth factor-I (IGF-I) and low IGF binding protein 3 (IGFBP-3) level have been associated with increased breast density in premenopausal women. Genetic polymorphisms in the IGF1 and IGFBP3 genes may influence breast and serum levels of these growth factors. The aims of this study were to determine whether polymorphic variations in the IGF1 and IGFBP3 genes are associated with breast density, and serum IGF-I and IGFBP-3 levels, and whether serum IGF-I and IGFBP-3 levels are associated with mammographic density. METHODS: A total of 441 white women, recruited from Women's College Hospital (Toronto, Ontario), enrolled in this study. Each woman completed a questionnaire, detailing information on age, menstrual history, hormone use, diet, and medical and mammography history. Blood samples were taken for DNA extraction to genotype the subjects for polymorphic variants in the two candidate genes, and for measurement of circulating levels of IGF-I and IGFBP-3. Mammographic films were retrieved from Women's College Hospital and digitized using a laser film scanner. The digitized images were assessed for breast density using a computer-assisted method. RESULTS: There was a positive association between serum IGFBP-3 levels and the number of A alleles at a previously described polymorphic locus in the promoter region of the IGFBP3 gene among premenopausal women (P = 0.01). There was also a positive trend in the mean percentage of breast density by the number of A alleles of the IGFBP3 gene among premenopausal women (P = 0.0005). Women with two A alleles had a 5-fold increase in the odds of having a percentage of breast density greater or equal to 28%, compared with women with no A allele (P = 0.002). However, there was no association between serum IGF-I and IGFBP-3 levels and breast density among premenopausal women (P > 0.05). CONCLUSIONS: This is the first study to report a strong relationship between a polymorphic gene locus (IGFBP3) and mammographic breast density. However, we could not confirm an association between serum IGF-I levels and breast density among premenopausal women, as demonstrated in previous studies.

Adult↗
PubMed2003

Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men.

Recent epidemiological studies suggest an association between higher blood levels of insulin-like growth factor I (IGF-I) and increased risk of prostate cancer. We evaluated the association between prediagnostic levels of IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) and prostate cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Within the same cohort (using different cases and controls who had sequential serum samples available) we also examined changes in serum IGF-I and IGFBP-3 levels over time by case status. The risk association study included incident prostate cancer cases (n = 100) diagnosed at least 5 years after baseline blood draw (range, 5-12 years; median 9 years) and frequency-matched (4:1) controls. The sequential serum study included all of the prostate cancer cases (n = 21) with prediagnostic (2-3 years before diagnosis) and diagnostic serum available, and pair-matched controls (1:1). An ELISA was used to quantitate serum levels of IGF-I and IGFBP-3 for both studies. The association between IGF-I or IGFBP-3 and prostate cancer risk was assessed using conditional logistic regression, and paired t tests were used to evaluate case-control differences in change in serum analytes over time. We found no significant association between either IGF-I or IGFBP-3 and prostate cancer risk. In a multivariate analysis, we observed an odds ratio of 0.52 (95% confidence interval, 0.23-1.16) for the fourth versus the first quartile of serum IGF-I. Serum IGF-I, but not IGFBP-3, increased significantly over time in cases (18% increase) but not controls (4% decrease; P = 0.02). In contrast to previous reports, we found no evidence to support a causal association between serum IGF-I or IGFBP-3 and the risk of prostate cancer. It is possible that serum IGF-I may be serving as a tumor marker rather than an etiologic factor in prostate cancer.

Aged↗
PubMed2003

Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation.

Large amounts of calcium are transferred to offspring by milk. This demand results in negative calcium balance in lactating mothers and is associated with rapid bone loss. The mechanisms of bone loss during lactation are only partly understood. Several studies have suggested that parathyroid hormone-related protein (PTHrP) might be secreted into the circulation by the lactating mammary gland and regulate bone turnover during lactation. Because mammary development fails in the absence of PTHrP, conventional PTHrP knockout mice cannot be used to address this possibility. To examine this hypothesis, we therefore used mice carrying a beta-lactoglobulin promoter-driven Cre transgene, one null PTHrP allele, and one floxed PTHrP allele. Expression of Cre specifically in mammary epithelial cells during late pregnancy and lactation resulted in efficient deletion of the PTHrP gene; mammary gland PTHrP mRNA and milk PTHrP protein were almost completely absent. Removal of PTHrP from the lactating mammary glands resulted in reductions in levels of circulating PTHrP and 1,25-dihydroxy vitamin D and urinary cAMP. In addition, bone turnover was reduced and bone loss during lactation was attenuated. We conclude that during lactation mammary epithelial cells are a source of circulating PTHrP that promotes bone loss by increasing rates of bone resorption.

Animals↗
PubMed2003

Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men.

The insulin-like growth factor (IGF) axis may play opposing roles in health and disease. The age-related declines in growth hormone and IGF-I may be associated with potentially deleterious changes in body composition and functioning, but recent studies suggest that IGF-I levels may be related to risk of prostate, colorectal, premenopausal breast, and possibly other cancers. Thus, we studied dietary influences on plasma IGF-I and IGF-I:IGF-binding protein-3 ratio in 753 men in the Health Professionals Follow-Up Study who completed a food frequency questionnaire. In this generally well-nourished population of middle-aged to elderly men, plasma IGF-I and IGF-I:IGF-binding protein-3 molar ratio tended to increase with higher intake of protein and minerals, including potassium, zinc, magnesium, calcium, and phosphorus. Men with relatively high intakes of total protein (top quintile) and minerals (top quintile of the five minerals combined) had a 25% higher mean plasma level of IGF-I compared with those in the low quintiles simultaneously. The major sources of animal protein, including milk, fish, and poultry, but not red meat, as well as total vegetable protein, were associated with an increase in IGF-I levels. Energy intake was positively related to plasma IGF-I level but only in men with body mass index <25 kg/m(2). The age-related decline in plasma IGF-I may be exacerbated by low intakes of protein and minerals. The potential role of these dietary factors on cancer risk through altering IGF-I levels requires study.

Aged↗
PubMed2003

Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer.

We examined whether selected polymorphisms in 11 candidate genes and serum levels of insulin-like growth factor I (IGF-I) help predict the presence of prostate cancer among patients prescreened with prostate-specific antigen (PSA) and digital rectal exam (DRE). We studied 1031 consecutive men who underwent one or more prostate biopsies because of an elevated PSA level (>4 ng/ml) or an abnormal DRE. Eleven candidate genes were examined, including the androgen receptor, SRD5A2, CYP17, CYP3A4, vitamin D receptor, PSA, GST-T1, GST-M1, GST-P1, IGF-I, and IGF binding protein 3. We also measured serum IGF-I levels before biopsy. Of the 1031 men, 483 had cancer on any biopsy (cases) and 548 men had no cancer (controls). Age, ethnicity, total PSA, and DRE result were strongly predictive of the presence of prostate cancer. The mean IGF-I level for cases (119.4 ng/ml) was lower than for controls (124.4 ng/ml, P = 0.05) and were not predictive for the presence of prostate cancer. We found no associations between the androgen receptor, SRD5A2, CYP17, CYP3A4, vitamin D receptor, GST-M1, GST-P1, and IGF binding protein 3 genotypes and prostate cancer risk. The adjusted odds ratios for having prostate cancer for patients with the GST-T1 and IGF-I variant alleles were 1.64 (95% confidence interval, 1.1-2.4; P = 0.01) and 1.70 (95% confidence interval, 1.1-2.7; P = 0.02), respectively. Nine of 11 candidate genes were not significantly predictive for prostate cancer in a clinical setting. The GST-T1 and IGF-I polymorphisms demonstrated modest associations with prostate cancer risk. IGF-I levels were not helpful in identifying patients with prostate cancer at the time of biopsy.

Adult↗
PubMed2002

Insulin-like growth factor-I antagonizes the antiproliferative effects of cyclooxygenase-2 inhibitors on BxPC-3 pancreatic cancer cells.

Cyclooxygenase (COX)-2 inhibitors demonstrate modest antineoplastic activity in experimental models of human malignancies, but little is known about factors that may confer resistance to their antiproliferative actions. We observed that fetal bovine serum antagonizes growth inhibition and G(1) arrest induced by two COX-2 inhibitors (NS-398 and celecoxib) on BxPC-3 pancreatic cancer cells. We investigated the hypothesis that insulin-like growth factor I (IGF-I), a major survival factor present in serum, mediates these effects. Treatment of BxPC-3 cells with 25 micro M celecoxib in 1% fetal bovine serum-containing medium for 48 h resulted in a approximately 40% decrease in cell viability. Coincubation of BxPC-3 cells with 25 micro M celecoxib and 50 ng/ml IGF-I resulted in complete attenuation of the celecoxib-associated decrease in cell viability. Cell cycle analysis revealed that this IGF-I-induced increase in cell viability was correlated with an IGF-I-induced inhibition of celecoxib-mediated G(1) arrest. Similar results were observed when another COX-2 inhibitor (50 micro M NS-398) was used. When IGF-binding protein-3 (an inhibitor of IGF-I bioactivity) was added in combination with 25 micro M celecoxib, enhanced growth inhibition was observed (approximately 60% decrease in cell viability). Treatment of BxPC-3 cells with a higher dose (50 micro M) of celecoxib for 24 h resulted in the induction of apoptosis, as assayed by flow cytometry and poly(ADP-ribose) polymerase cleavage. Addition of 50 ng/ml IGF-I resulted in a complete attenuation of celecoxib-induced apoptosis. The protection from celecoxib-induced apoptosis by IGF-I correlated with an increase in the levels of the activated antiapoptotic protein Akt. These results suggest that alterations of IGF-I levels or IGF-I receptor signal transduction modulate the antineoplastic actions of COX-2 inhibitors.

Antineoplastic Agents↗
PubMed2002

Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer.

BACKGROUND: Plasma levels of insulin-like growth factor-I (IGF-I) have been associated with the risk of prostate cancer. However, the association of IGF-I with specific tumor stage and grade at diagnosis, which correlate with risk of recurrence and mortality, has not been studied rigorously. To determine whether plasma levels of IGF-I and its main circulating binding protein, IGF binding protein-3 (IGFBP-3), predict more aggressive forms of prostate cancer, we investigated the association between plasma levels of each and specific stages and grades of prostate cancer. METHODS: We examined 530 case patients and 534 control subjects in a nested case-control study in the prospective Physicians' Health Study. Patients with prostate cancer diagnosed from 1982 through 1995 were matched to control subjects by age and smoking status. IGF-I and IGFBP-3 were measured in prospectively collected plasma samples. Conditional logistic regression models were used to estimate the relative risks (RRs) for prostate cancer associated with IGF-I and IGFBP-3, stratified on grade (Gleason score > or = 7 versus <7) and stage (early = stage A or B prostate cancer versus advanced = stage C or D prostate cancer). All statistical tests were two-sided. RESULTS: Plasma levels of IGF-I and IGFBP-3 were predictors of advanced-stage prostate cancer (RR = 5.1, 95% confidence interval [CI] = 2.0 to 13.2 for highest versus lowest quartiles of IGF-I; RR = 0.2, 95% CI = 0.1 to 0.6 for highest versus lowest quartiles of IGFBP-3) but not of early-stage prostate cancer. Neither was differentially associated with Gleason score. Men with high IGF-I levels and low IGFBP-3 levels had an RR for advanced-stage prostate cancer of 9.5 (95% CI = 1.9 to 48.4) compared with men with low levels of both. Combining IGF-I and IGFPB-3 measurements with a standard prostate-specific antigen (PSA) measurement for prostate cancer screening increased the specificity (from 91% to 93%) but decreased sensitivity (from 40% to 36%) compared with measurement of PSA alone. CONCLUSIONS: Circulating levels of IGF-I and IGFBP-3 may predict the risk of developing advanced-stage prostate cancer, but their utility for screening patients with incident prostate cancer may be limited.

Adult↗
PubMed2002

Reduced growth of human sarcoma xenografts in hosts homozygous for the lit mutation.

BACKGROUND AND OBJECTIVES: Prior studies have shown that sarcoma growth can be stimulated by insulin-like growth factor-I (IGF-I). To extend this line of research, we carried out in vivo growth studies of primary human sarcoma in immunosuppressed control and IGF-I-deficient mice. METHODS: Human sarcoma specimens (one osteosarcoma and seven soft tissue sarcomas) were harvested in the operating room and implanted in immunosuppressed mice. Second-generation sarcomas were transplanted to control (GH replete lit/+ mice) and to experimental (GH/IGF-I-deficient lit/lit) animals. When tumors reached 1,000 mm(3) in one group, average tumor size was compared in the two groups. IGF-I receptor expression was measured by RT-PCR and IGF-I receptor binding sites were assayed by radiolabeled IGF-I. RESULTS: Five of eight sarcomas demonstrated reduced growth in the GH/IGF-I-deficient lit/lit animals. In four of the five sarcomas that demonstrated growth inhibition, IGF-R was elevated relative to placenta or a positive control cell line (MCF-7, which is known to be responsive to IGF-I in vitro and in vivo). In three of the five sarcomas that demonstrated growth suppression, IGF-R was elevated twofold after implantation in the experimental IGF-I-deficient animals. CONCLUSIONS: The GH-IGF axis may be an important stimulator of tumor growth in sarcomas. These experiments suggest that IGF suppression may inhibit sarcoma growth in vivo.

Animals↗
PubMed2002

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 for prostate cancer detection in patients undergoing prostate biopsy.

PURPOSE: Laboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy. MATERIALS AND METHODS: A total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions. RESULTS: Mean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3. CONCLUSIONS: Our data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.

Aged↗
PubMed2002

Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel.

PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug resistance-associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. EXPERIMENTAL DESIGN: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed/progressive disease within 6 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous i.v. infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks. RESULTS: Thirty-seven patients received study treatment and 35 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median nadir ANC cycle 1 of 0.76 x 10(9) cells/liter and a 40% overall incidence of Grade 4 neutropenia. Nonhematological side effects (asthenia, paresthesia, headache, myalgia, nausea, and diarrhea) were generally mild to moderate and reversible. Paclitaxel AUC (16.8 +/- 5.0 microg x h/ml) and clearance (5.1 +/- 1.3 liters/h/m(2)) during the first treatment cycle were comparable with standard 175 mg/m(2) paclitaxel administered in a 3-h schedule. Four patients achieved partial responses (three of the four had progressive disease on prior paclitaxel) with a mean response duration of 5.5 months. CONCLUSIONS: The 11.4% (4 of 35) objective response rate observed in this study suggests that VX-710 can resensitize a subgroup of paclitaxel-refractory patients to paclitaxel. The safety and pharmacokinetics of the VX-710/pacitaxel regimen support further evaluation in breast cancer patients with initial paclitaxel therapy to prevent emergence of the MDR phenotype in recurrent disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-Carotene and Retinol Efficacy Trial Cohort.

Recent prospective studies have suggested that insulin-like growth factor (IGF)-I levels are related to risk of some epithelial cancers. We previously reported in a case-control study a significant association between IGF-I level and lung cancer risk, with a 2-fold increased risk in the highest quartile. We now report the results of a lung cancer case-control study nested in the placebo arm of the beta-Carotene and Retinol Efficacy Trial in heavy smokers. We identified 159 cases for whom sera had been collected at least 3 years before diagnosis and for whom 2 suitable controls/case (final number, 297) could be matched from the same study arm on age (within 5-year intervals), sex, ethnicity, year of enrollment into the beta-Carotene and Retinol Efficacy Trial, year of blood draw, and exposure category (smoking or asbestos). The cases were significantly heavier smokers than the controls (mean pack-years, 58.7 and 45.9, respectively; P < 0.001). An inverse relationship between IGF-I level and age was evident only for former smokers, and not for those who were current smokers at the time of blood draw. Both IGF-I and IGF-binding protein (IGFBP)-3 levels were higher in cases than in controls, but none of the differences achieved statistical significance. The odds ratios for IGF-I were around unity, except for subsets of heaviest smokers and those who had quit smoking for the longest period of time, in whom there were elevated risks in the second to fourth quartiles of IGF-I relative to the first quartile (odds ratios, 2.21-2.91), although again, none achieved statistical significance. For younger subjects, IGF-I was inversely associated with lung cancer risk in the models that also controlled for IGFBP-3. Elevated risks for lung cancer were noted in the highest quartile of IGFBP-3 level, and these tended to be higher in current smokers and more recent quitters. These results do not support the conclusions of our prior case-control study. It is possible that current smoking or recent cessation may exert a suppressive effect on IGF-I levels (notably in younger subjects with higher baseline levels) that may obscure a relatively modest association between IGF-I level and lung cancer risk. On the other hand, risks associated with elevated IGFBP-3 level tended to be higher in current smokers and more recent quitters. This trend toward a positive association with IGFBP-3 level is unexpected and requires further investigation. Finally, from these data, we cannot exclude the possibility that risk of lung cancer in nonsmokers may be related to IGF-I levels.

Aged↗
PubMed2002

Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells.

BACKGROUND: The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) is useful in the treatment of ErbB2-overexpressing breast cancers, but its efficiency is limited because development of resistance is common. In order to study the possibility of improving the efficacy of therapies directed against HER2/erbB2, we investigated the effects of co-targeting this receptor and the insulin-like growth factor 1 receptor (IGF-1R), a widely-expressed protein tyrosine kinase with important roles in suppression of apoptosis and stimulation of proliferation. MATERIAL/METHODS: The experimental strategy involved combining trastuzumab treatment and reduction of IGF-1R signaling through incremental heat-induced expression of the dominant-negative IGF-1 receptor 486/STOP under the control of the heat-sensitive Drosophila HSP70 promoter, in HER2/erbB2-overexpressing MCF7her18 breast cancer cells. RESULTS: Isobologram analysis of combinatorial treatment data revealed a strong synergistic interaction between trastuzumab treatment and the induction of the dominant-negative IGF-1R expression, resulting in potentiation of growth inhibition in transfected cancer cells. CONCLUSIONS: These observations support the concept that simultaneously co-targeting tyrosine kinase receptors may be therapeutically useful, and provide a specific rationale for combining IGF-1R and HER2/erbB2 targeting strategies in anti-neoplastic approaches.

Antibodies, Monoclonal↗