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1.
Clin Cancer Res ; 25(10): 2988-2995, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30224341

ABSTRACT

PURPOSE: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/ß-actin mRNA expression level and region. RESULTS: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61-1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56-1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56-1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51-1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93-1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20-2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. CONCLUSIONS: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Biomarkers, Tumor/blood , Camptothecin/administration & dosage , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , DNA-Binding Proteins/blood , Endonucleases/blood , Female , Fluorouracil/administration & dosage , Humans , Irinotecan/administration & dosage , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Prognosis , Survival Rate , Vascular Endothelial Growth Factor A/blood
2.
Cancer Genet ; 224-225: 12-20, 2018 08.
Article in English | MEDLINE | ID: mdl-29778231

ABSTRACT

Clinical diagnostic exome sequencing (DES) has been effective in diagnosing individuals with suspected genetic conditions; nevertheless little has been described regarding its clinical utility in individuals with a personal and family history of cancer. This study aimed to assess diagnostic yield and clinical characteristics of pediatric and adult patients undergoing germline DES for hereditary cancer. We retrospectively reviewed 2171 patients referred for DES; cases with a personal and/or family history of cancer were further studied. Of 39 cancer patients, relevant alterations were found in eight individuals (21%), including one (3%) positive pathogenic alteration within a characterized gene, two (5%) uncertain findings in characterized genes, and five (13%) alterations in novel candidate genes. Two of the 5 pediatric patients, undergoing testing, (40%) had findings in novel candidate genes, with the remainder being negative. We include brief case studies to illustrate the variety of challenging issues related to these patients. Our observations demonstrate utility of family-based exome sequencing in patients for suspected hereditary cancer, including familial co-segregation analysis, and comprehensive medical review. DES may be particularly useful when traditional approaches do not result in a diagnosis or in families with unique phenotypes. This work also highlights the importance and complexity of analysis of uncharacterized genes in exome sequencing for hereditary cancer.


Subject(s)
Genetic Testing/methods , Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Exome , Female , Genetic Predisposition to Disease , Humans , Infant , Male , Middle Aged , Neoplasms/pathology , Young Adult
4.
J Thorac Oncol ; 12(6): 932-942, 2017 06.
Article in English | MEDLINE | ID: mdl-28315738

ABSTRACT

INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. METHODS: Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. RESULTS: The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. CONCLUSION: Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.


Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinosarcoma/genetics , Genomics/methods , Lung Neoplasms/genetics , Mutation , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinosarcoma/pathology , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Prospective Studies , Proto-Oncogene Mas
5.
Head Neck ; 39(3): E40-E44, 2017 03.
Article in English | MEDLINE | ID: mdl-28006087

ABSTRACT

BACKGROUND: Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options. METHODS: We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case. RESULTS: Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control. CONCLUSION: Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. © 2016 Wiley Periodicals, Inc. Head Neck 39: E40-E44, 2017.


Subject(s)
Adenoma, Pleomorphic/drug therapy , Molecular Targeted Therapy/methods , Receptor, ErbB-2/drug effects , Receptor, ErbB-2/genetics , Salivary Gland Neoplasms/drug therapy , Trastuzumab/therapeutic use , Adenoma, Pleomorphic/genetics , Adenoma, Pleomorphic/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy, Needle , Follow-Up Studies , Humans , Immunohistochemistry , Male , Positron Emission Tomography Computed Tomography/methods , Risk Assessment , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/pathology , Treatment Outcome
6.
Fam Cancer ; 16(3): 395-399, 2017 07.
Article in English | MEDLINE | ID: mdl-27866340

ABSTRACT

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.


Subject(s)
Carcinoma, Small Cell/genetics , DNA Helicases/genetics , Genetic Predisposition to Disease/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adult , Female , Humans , Hypercalcemia , Mutation , Pedigree , Young Adult
7.
Cancer Chemother Pharmacol ; 78(4): 815-24, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27566701

ABSTRACT

PURPOSE: Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B). METHODS: Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory). RESULTS: A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %). CONCLUSIONS: LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS. GOV IDENTIFIER: NCT01288989.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Neoplasms/drug therapy , Vascular Endothelial Growth Factor Receptor-3/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Cohort Studies , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Male , Maximum Tolerated Dose , Middle Aged , Treatment Outcome , Vascular Endothelial Growth Factor Receptor-3/immunology
8.
Gynecol Oncol ; 141(3): 454-460, 2016 06.
Article in English | MEDLINE | ID: mdl-26975901

ABSTRACT

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02). CONCLUSIONS: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.


Subject(s)
Carcinoma, Small Cell/genetics , Carcinoma, Small Cell/therapy , Hypercalcemia/genetics , Hypercalcemia/therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapy , Adolescent , Adult , Age Factors , Carcinoma, Small Cell/pathology , Child , Cohort Studies , DNA Helicases/genetics , Female , Germ-Line Mutation , Humans , Hypercalcemia/pathology , Kaplan-Meier Estimate , Neoplasm Staging , Nuclear Proteins/genetics , Ovarian Neoplasms/pathology , Prognosis , Transcription Factors/genetics , Young Adult
9.
Cancer Med ; 3(4): 988-97, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24905030

ABSTRACT

Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/adverse effects , Colorectal Neoplasms/pathology , Fatigue/chemically induced , Female , Humans , Male , Middle Aged , Receptor, IGF Type 1/immunology , Treatment Outcome
10.
Invest New Drugs ; 30(3): 1211-5, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21552992

ABSTRACT

BACKGROUND: Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. PATIENTS AND METHODS: We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. RESULTS: Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. CONCLUSION: Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.


Subject(s)
Colorectal Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/pathology , Dasatinib , Female , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyrimidines/adverse effects , Thiazoles/adverse effects , src-Family Kinases/antagonists & inhibitors
11.
J Thorac Oncol ; 5(12): 1994-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20975604

ABSTRACT

INTRODUCTION: Based on favorable preliminary clinical data and the need to identify effective, well-tolerated neoadjuvant regimens for patients with locally advanced esophageal cancer, this clinical trial was undertaken. METHODS: This phase II study tested 500 mg/m neoadjuvant pemetrexed intravenously and carboplatin with an area under the curve of 6 intravenously on days 1 and 22 in conjunction with concomitant radiation of 5040 centigray, which was given in 28 daily fractions of 180 centigray. The primary endpoint was the rate of pathologic complete response. RESULTS: This trial closed early because, during an interim analysis, the primary endpoint fell short. However, 26 eligible patients were accrued. Twenty (74%) were men. Performance scores of 0, 1, and 2 were seen in 16 (59%), 9 (33%), and 2 (7%), respectively. Among eligible patients, 6 of 26 (23%; 95% confidence interval 9-44%) demonstrated a pathologic complete response. Twenty-two underwent a complete cancer resection. The median survival was 17.8 months (95% confidence interval: 12.2-30.7 months). In the neoadjuvant setting, 22 patients had at least one grade 3 or worse adverse event, and 8 patients had at least one grade 4 event. Postoperatively (within 30 days of surgery), there were three deaths, one grade 4 event (thrombosis), and three grade 3 events. CONCLUSIONS: The neoadjuvant regimen tested within this phase II trial demonstrated antineoplastic activity but fell short of yielding a complete pathologic response rate that merits further testing.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/therapy , Esophagogastric Junction , Adult , Aged , Aged, 80 and over , Carboplatin/administration & dosage , Combined Modality Therapy , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Male , Middle Aged , Pemetrexed , Radiotherapy Dosage
12.
Gynecol Oncol ; 117(1): 37-40, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20117828

ABSTRACT

OBJECTIVES: To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. METHODS: This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0-1 prior chemotherapy regimens, and ECOG performance status

Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma/drug therapy , Carcinosarcoma/drug therapy , Pyridines/therapeutic use , Uterine Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Benzenesulfonates/adverse effects , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/adverse effects , Sorafenib , Survival Rate
13.
Mol Cancer Res ; 7(8): 1285-93, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19671688

ABSTRACT

Uracil DNA glycosylase (UNG) is the primary enzyme responsible for removing uracil residues from DNA. Although a substantial body of evidence suggests that DNA damage plays a role in cancer cell apoptosis, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in cell survival. To test the hypothesis that the repair of DNA damage associated with uracil misincorporation is critical for cancer cell survival, we used small interfering RNA (siRNA) to target the human UNG gene. In a dose-dependent and time-dependent manner, siRNA specifically inhibited UNG expression and modified the expression of several genes at both mRNA and protein levels. In LNCaP cells, p53, p21, and Bax protein levels increased, whereas Bcl2 levels decreased. In DU145 cells, p21 levels were elevated, although mutant p53 and Bax levels remained unchanged. In PC3 cells, UNG inhibition resulted in elevated p21 and Bax levels. In all three cell lines, UNG inhibition reduced cell proliferation, induced apoptosis, and increased cellular sensitivity to genotoxic stress. Furthermore, an in vitro cleavage experiment using uracil-containing double-stranded DNA as a template has shown that siRNA-mediated knockdown of UNG expression significantly reduced the uracil-excising activity of UNG in human prostate cancer cells, which was associated with DNA damage analyzed by comet assay. Taken together, these findings indicate that RNA interference-directed targeting of UNG is a convenient, novel tool for studying the biological role of UNG and raises the potential of its application for prostate cancer therapy.


Subject(s)
Apoptosis , DNA Damage , Gene Knockdown Techniques , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/genetics , RNA, Small Interfering/metabolism , Uracil-DNA Glycosidase/genetics , Apoptosis/drug effects , Bromodeoxyuridine/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydrogen Peroxide/pharmacology , Male , Prostatic Neoplasms/pathology , RNA Interference/drug effects , Tumor Suppressor Protein p53/metabolism , Uracil/metabolism
14.
Invest New Drugs ; 24(2): 141-9, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16514482

ABSTRACT

PURPOSE: Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer. EXPERIMENTAL DESIGN: IL-2 naïve patients were given 11 x 10(6) IU subcutaneously of IL-2 on days 1-4, 8-11, and 15-18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-gamma. Response evaluation was performed every 3 cycles. RESULTS: Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88-120) and the median survival was 452 days (95% CI = 424-480). There was no significant boosting effect of Bryostatin-1 on lymphocytes. CONCLUSIONS: The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bryostatins/administration & dosage , Carcinoma, Renal Cell/drug therapy , Interleukin-2/administration & dosage , Kidney Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bryostatins/adverse effects , Carcinoma, Renal Cell/immunology , Cytokines/biosynthesis , Dose-Response Relationship, Drug , Female , Humans , Interleukin-2/adverse effects , Kidney Neoplasms/immunology , Male , Middle Aged , Neoplasm Metastasis , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Treatment Failure
15.
Cancer ; 103(1): 111-8, 2005 Jan 01.
Article in English | MEDLINE | ID: mdl-15558814

ABSTRACT

BACKGROUND: Gemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6-month survival, response, and toxicity associated with a combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA). METHODS: A 4-week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5-FU by intravenous push after LV. RESULTS: Forty-two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1-21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for > or = 8 weeks. No treatment-related deaths occurred. Thirty-two patients had disease progression and 38 died after a median follow-up of 20 months (range, 1.4-24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4-6.6%). The median survival period was 9.7 months (95% CI, 7-12%). CONCLUSIONS: This combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived > or = 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5-FU, and LV had benefit equivalent to gemcitabine alone.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Deoxycytidine/analogs & derivatives , Gallbladder Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biliary Tract Neoplasms/pathology , Cholangiocarcinoma/pathology , Deoxycytidine/administration & dosage , Female , Fluorouracil/administration & dosage , Gallbladder Neoplasms/pathology , Humans , Infusions, Intravenous , Injections, Intravenous , Leucovorin/administration & dosage , Male , Middle Aged , Survival Analysis , Gemcitabine
16.
J Clin Oncol ; 21(5): 914-20, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12610193

ABSTRACT

PURPOSE: To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy. PARTICIPANTS AND METHODS: Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment. RESULTS: Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P =.73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P =.12). CONCLUSION: Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.


Subject(s)
Bupropion/therapeutic use , Dopamine Uptake Inhibitors/therapeutic use , Nicotine/administration & dosage , Smoking Cessation/methods , Smoking Prevention , Adolescent , Adult , Aged , Aged, 80 and over , Delayed-Action Preparations , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Middle Aged , Recurrence , Smoking/epidemiology , Treatment Outcome
17.
Am J Clin Oncol ; 25(6): 547-51, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12477995

ABSTRACT

A randomized phase III study was conducted to assess the addition of molgramostim (GM-CSF) to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in terms of response rate, progression-free survival, and survival in women with advanced, recurrent, or metastatic carcinoma of the cervix or vagina. Patients received four 4-week cycles of methotrexate 30 mg/m2 IV days 1, 15, 22; vinblastine 3 mg/m2 IV days 2, 15, 22; doxorubicin 30 mg/m2 IV day 2; and cisplatin 70 mg/m2 IV day 2 with or without GM-CSF 5 microg/kg every 12 hours subcutaneously days 3 to 12. They were then reevaluated for operability. Those who were not surgical candidates were offered additional chemotherapy until progression or toxicity. Those who were surgical candidates were offered surgical resection of remaining tumor followed by involved-field external beam irradiation to sites of no prior irradiation and intraoperative irradiation to sites of prior external beam irradiation. This trial closed after 36 eligible patients were entered because of poor accrual. Although more than 40% of patients on each arm received fewer than four cycles of MVAC, the clinical response rate was 78% (95% CI: 52-94%) and 50% (95% CI: 26-74%) for MVAC and MVAC + GM-CSF, respectively; the median time to progression was 10.2 and 11.8 months, respectively; and median survival was 13.8 and 16.0 months, respectively. Toxicity was substantial, with more than 40% experiencing grade III to IV leukopenia, and nearly 40% experiencing grade III to IV stomatitis. MVAC with or without GM-CSF support achieves high response rates in patients with advanced, recurrent, or metastatic cervical carcinoma despite dose reductions and deletions. Its progression-free survival and overall survival rates appear promising. These results need to be confirmed within a large randomized phase III clinical trial.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Recombinant Proteins/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Vaginal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cisplatin/administration & dosage , Combined Modality Therapy , Doxorubicin/administration & dosage , Female , Humans , Methotrexate/administration & dosage , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/radiotherapy , Neoplasm Recurrence, Local/surgery , Survival Analysis , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/radiotherapy , Uterine Cervical Neoplasms/surgery , Vaginal Neoplasms/pathology , Vaginal Neoplasms/radiotherapy , Vaginal Neoplasms/surgery , Vinblastine/administration & dosage
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