Biomedical subjects

Sydney Finkelstein

Publications and source records attributed to Sydney Finkelstein.

At least 19 recordsLinked to original sources

PubMed2006

Endoscopic ultrasound-guided fine needle aspirate microsatellite loss analysis and pancreatic endocrine tumor outcome.

BACKGROUND & AIMS: The clinical course of pancreatic endocrine tumor (PET) varies depending on tumor aggressiveness, disease extent, and possibly accumulated molecular alterations. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) results, although accurate in diagnosing PET, correlate poorly with PET outcome. The role of detecting key molecular abnormalities in predicting PET behavior and clinical outcome from EUS-FNA material remains unknown. METHODS: Patients with confirmed PET who underwent EUS-FNA during a 32-month period were included. Patient demographics and clinical data were recorded and follow-up information was obtained by contacting their physician to evaluate disease progression. Representative tumor cells were microdissected from the FNA material. DNA was harvested and amplified, targeting a panel of 17 polymorphic microsatellite markers on chromosomes 1p, 3p, 5q, 9p, 10q, 11q, 17p, 17q, 21q, and 22q. The polymerase chain reaction products were subjected to fluorescent capillary gel electrophoresis to detect microsatellite loss. The fractional allelic loss (FAL) was calculated. RESULTS: Twenty-five patients were studied. Thirteen were classified histologically as benign PET limited to the pancreas and 12 as malignant PET (invasive or metastatic). The mean FAL in the benign and malignant PET was 0.03 and 0.37 (P<.0001), respectively. In addition, the mean FAL was significantly greater in those with disease progression as compared with patients with stable disease (0.45 vs 0.09 respectively, P<.0001). CONCLUSIONS: Microsatellite loss analysis of EUS-FNA material from PET can be performed reliably and an FAL value of more than 0.2 is associated with disease progression. This technique may have value in the preoperative assessment and risk stratification of patients with PET.

Adult↗

PubMed2005

Molecular analysis of primary and recurrent giant cell tumors of bone.

The status of microsatellite markers located on chromosomes 1p36, 3p25, 5q23, 9p22, 10q23, 10q24, 17p13, and 19q12 was used to determine loss of heterozygosity (LOH) in primary giant cell tumors (GCT) of bone in 12 patients. The cases included primary, locally recurrent, and metastatic GCT; three tumors were classified as malignant GCT, based on their morphological features. Microdissection was performed on 24 paraffin-embedded tissue samples. An average of three separate topographic sites were microdissected from each tumor. Case selection in each instance was based on the availability of paired samples of tumor in primary GCTs and their corresponding recurrences, and the presence of normal tissue. The number of cases studied is too small for statistical studies, and thus the analysis is descriptive. All cases were informative for >80% of the markers used. Both primary GCTs and local recurrences and lung metastases displayed LOH of three or more markers, and intratumoral heterogeneity was frequent. Fractional allelic losses (FAL) were not different in recurrent and nonrecurrent GCT. FAL was greatest (>30%) in the metastatic group of GCT. Allelic losses of 1p, 9q, and 19q regions were frequent in all groups. LOH of 17p (in proximity to the p53 locus) and 9p occurred exclusively in the pulmonary metastases from GCT. LOH of 9q and 19q was present in primary as well as recurrent GCTs and in one malignant GCT. Involvement of 1p (including MYCL) and 9q regions has not been previously reported in GCT of bone. The pattern of LOH evident in the 17 markers used in the present study suggests that GCT with malignant features may follow an evolutionary pathway similar to the usual primary GCT of bone.

Adolescent↗

PubMed2005

Molecular diagnosis of solid and cystic lesions of the pancreas.

Pancreatic cancer presents at a clinically advanced stage. Diagnosis often is delayed in those who undergo several negative investigations, and at times, the diagnosis ultimately is made at surgery. Tumor suppressor-linked microsatellite allelic loss analysis appears to improve the diagnostic accuracy of inconclusive cytology specimens. Science, however, still suffers from the lack of a reliable biomarker for the purpose of screening and early detection. The continued study of sera and pancreatic juice hopefully will lead to the discovery of molecular biomarkers capable of diagnosing preclinical disease in at-risk groups.The ability to predict the underlying biologic behavior of pancreatic cystic neoplasia is less than ideal. Tumor suppressor-linked microsatellite allelic loss and telomerase analysis show promise, but they have not been studied extensively. Proteomic analysis of pancreatic cyst fluid, although not yet reported, also may prove valuable in guiding clinical management.

Genetic Markers↗

PubMed2005

The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology.

BACKGROUND & AIMS: Current methods to detect malignancy in mucinous cystic neoplasms of the pancreas remain inadequate. The role of detailed molecular analysis in this context was investigated. METHODS: Endoscopic ultrasound-guided pancreatic cyst aspirates were prospectively collected during a period of 19 months and studied for cytology, carcinoembryonic antigen level, and molecular analysis. Molecular evaluation incorporated DNA quantification (amount and quality), k-ras point mutation, and broad panel tumor suppressor linked microsatellite marker allelic loss analysis by using fluorescent capillary electrophoresis. The sequence of mutation acquisition was also calculated on the basis of a clonal expansion model, and comparison was made to the final pathology. RESULTS: Thirty-six cysts with confirmed histology were analyzed. There were 11 malignant, 15 premalignant, and 10 benign cysts. Malignant cysts could be differentiated from premalignant cysts on the basis of fluid carcinoembryonic antigen level (P=.034), DNA quality (P=.009), number of mutations (P=.002), and on the sequence of mutations acquired (P<.001). Early k-ras mutation followed by allelic loss was the most predictive of a malignant cyst (sensitivity, 91%; specificity, 93%). CONCLUSIONS: Malignant cyst fluid contains adequate DNA to allow mutational analysis. A first hit k-ras mutation followed by allelic loss is most predictive of the presence of malignancy in a pancreatic cyst. This approach should serve as an ancillary tool to the conventional work-up of pancreatic cysts. Cumulative amount and timing of detectable mutational damage can assist in diagnosis and clinical management.

Carcinoembryonic Antigen↗

PubMed2005

Patterns of allelic loss of synchronous adenocarcinomas of the lung.

Distinction of multiple primary lung carcinomas from intrapulmonary metastases using empiric clinical and histopathologic criteria can be difficult. Recent advances have provided several molecular markers that can be used for clonal analysis of separate tumor nodules and enhance tumor staging and subsequent treatment and prognosis. To address this issue, we performed a microdissection-based allelotyping of 20 cases of histologically similar, pathologic stage T4 adenocarcinomas (ADCs). Loss of heterozygosity (LOH) analysis included a panel of 15 polymorphic microsatellite markers located on 1p, 3p, 5q, 9p, 9q, 10q, 17p, and 22q. The tumor size, visceral pleural and angiolymphatic invasion, lymph node status, outcome, and survival were assessed. Allelotypes of 60 cases of solitary primary non-small cell lung carcinomas (NSCLC) (stages I-II) were used to define the percentage of discordant LOH patterns within solitary primary lung carcinoma that would discriminate between survivors and nonsurvivors. These criteria were used in the analysis of pathologic stage T4 ADC. Two groups of stage T4 cases were created: molecularly homogenous (< or = 40% discordances) (14 cases, 70%), and molecularly heterogenous (>40% discordances) (6 cases, 30%). Molecularly homogenous tumors were more frequently associated with visceral pleural invasion (92% vs. 8%) (P = 0.018). Allelotype did not correlate with age, gender, tumor size, tumor differentiation, lymph node status, angiolymphatic invasion, survival, or outcome. Our study showed that discordant and concordant genotypic profiles exist in morphologically similar synchronous ADC of the lung.

Adenocarcinoma↗

PubMed2005

Comparative mutational analysis of pulmonary scar epithelium, bronchioloalveolar carcinomas, and invasive well-differentiated pulmonary adenocarcinomas: a molecular approach to diagnostically challenging cases.

Discrimination of invasive well-differentiated adenocarcinoma (IAD) from reactive bronchioloalveolar epithelium entrapped in pulmonary scars (PSE) may be difficult on routine histology, especially on small biopsies. Ancillary studies to help in this regard are desirable. Whereas IADs have been shown to harbor cumulative mutational damage of tumor suppressor genes, little is known about molecular changes in PSEs. In this study, we compared cumulative loss of heterozygosity (LOH) of tumor suppressor genes in PSEs (N = 12), bronchioloalveolar carcinomas (BACs, N = 15) and stage 1 IADs (N = 7). Unstained serial sections were microdissected to obtain lesional and normal tissue DNA. PCR was performed for up to 16 polymorphic markers. An allelic ratio of < 0.5 or >2.0 was designated as LOH. Fractional allelic loss (FAL) was calculated for each case as the number of markers with LOH divided by the total number of informative markers. Mean percentage of informative markers was 76.8%. PSEs showed significantly lower mean FAL compared with BACs and IADs (3.0% vs. 20.4% and 28.5%, respectively; P < 0.003). Only 1 case of PSE showed LOH of one marker in two different areas, whereas the majority of allelic losses in the neoplasms were present in two or more microdissected foci. Our study shows that PSEs harbor LOH of tumor suppressor genes at relatively low rates and in a random distribution compared with BACs and IADs, which show consistent allelic losses, and high FALs. These molecular differences may serve as an adjunct to histology in challenging glandular lesions of the lung.

Adenocarcinoma↗

PubMed2005

The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma.

The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted.

Adenocarcinoma↗

PubMed2004

High throughput screening of methylation status of genes in prostate cancer using an oligonucleotide methylation array.

Recent work using high-throughput microarray technology has discovered altered expression of a large number of genes in prostate cancer. Many of these alterations may be the consequence of changes in methylation status in the CpG islands of promoter or exon 1 regions of these genes. In order to determine the methylation status of a large number of genes and ESTs we combined the principle of match/mismatch hybridization with the technique of whole genome labeling to develop a highly specific oligonucleotide-based methylation microarray. Using this array, we analyzed the methylation status of 105 genes and ESTs in three prostate cancer cell lines. Between 32 and 47% of these genes and ESTs were methylated in these cell lines. By correlating the methylation status of this array with the results of Affymetrix expression arrays of three prostate cancer cell lines, we determined that methylation of genes played a significant role (37%) in down-regulating the expression of certain genes in prostate cancer. We also tested this array on a number of primary prostate tissue samples. Our results indicated that a subset of genes in this microarray (25/105) were methylated in all prostate cancer samples but not in normal prostate, suggesting the potential significance of alterations in the methylation status of certain genes in the development of prostate cancer.

Acetylation↗

PubMed2004

Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy.

PURPOSE: The incidence of prostate cancer is frequent, occurring in almost one-third of men older than 45 years. Only a fraction of the cases reach the stages displaying clinical significance. Despite the advances in our understanding of prostate carcinogenesis and disease progression, our knowledge of this disease is still fragmented. Identification of the genes and patterns of gene expression will provide a more cohesive picture of prostate cancer biology. PATIENTS AND METHODS: In this study, we performed a comprehensive gene expression analysis on 152 human samples including prostate cancer tissues, prostate tissues adjacent to tumor, and organ donor prostate tissues, obtained from men of various ages, using the Affymetrix (Santa Clara, CA) U95a, U95b, and U95c chip sets (37,777 genes and expression sequence tags). RESULTS: Our results confirm an alteration of gene expression in prostate cancer when comparing with nontumor adjacent prostate tissues. However, our study also indicates that the gene expression pattern in tissues adjacent to cancer is so substantially altered that it resembles a cancer field effect. CONCLUSION: We also found that gene expression patterns can be used to predict the aggressiveness of prostate cancer using a novel model.

Adult↗

PubMed2004

Molecular diagnosis of solid and cystic lesions of the pancreas.

Pancreatic cancer presents at a clinically advanced stage. Diagnosis often is delayed in those who undergo several negative investigations, and at times, the diagnosis ultimately is made at surgery. Tumor suppressor-linked microsatellite allelic loss analysis appears to improve the diagnostic accuracy of inconclusive cytology specimens. Science, however, still suffers from the lack of a reliable biomarker for the purpose of screening and early detection. The continued study of sera and pancreatic juice hopefully will lead to the discovery of molecular biomarkers capable of diagnosing pre-clinical disease in at-risk groups. The ability to predict the underlying biologic behavior of pancreatic cystic neoplasia is less than ideal. Tumor suppressor-linked microsatellite allelic loss and telomerase analysis show promise, but they have not been studied extensively. Proteomic analysis of pancreatic cyst fluid, although not yet reported, also may prove valuable in guiding clinical management.

Biomarkers↗

PubMed2004

Allelic loss of tumor suppressor genes in ameloblastic tumors.

Ameloblastoma is an odontogenic tumor with a variety of histologic appearances and an unpredictable biologic behavior. Little is known about allelic losses of tumor suppressor genes in ameloblastomas. This study surveyed DNA damage in ameloblastomas and correlated this with histologic sub-type and clinical outcome. There were 12 ameloblastomas (two peripheral, eight solid, and two unicystic) and three ameloblastic carcinoma studied for loss of heterozygosity of tumor suppressor genes on chromosomes 1p, 3p, 9p,10q, and 17p (L-myc, hOGG1, p16, pten, and p53). The frequency of allelic loss and the intratumoral heterogeneity were calculated. L-myc (71% frequency of allelic loss) and pten (62% frequency of allelic loss) had the most frequent allelic losses. Overall frequency of allelic loss and intratumoral heterogeneity were higher in mandibular and in unicystic tumors and lower in tumors that recurred/metastasized. The rate of allelic loss in the three carcinomas was similar to that seen in benign tumors. The frequency of allelic loss and intratumoral heterogeneity did not correlate with age, gender, histologic subtype, or prognosis. Since tumors that behaved aggressively did not harbor more allelic losses, it is likely that DNA damage in ameloblastomas and ameloblastic carcinomas is sporadic and cumulative. We conclude that other genetic or epigenetic mechanisms may be responsible for malignant behavior in ameloblastic carcinomas.

Adult↗

PubMed2004

Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial.

BACKGROUND: To determine the response rate of trastuzumab and irinotecan in HER-2/neu overexpressing advanced colorectal cancer (CRC), determine the frequency of HER-2/neu expression in CRC, and evaluate the pharmacokinetics of trastuzumab in a phase II study. PATIENTS AND METHODS: Patients were screened for HER-2/neu by immunohistochemistry (DAKO HercepTest). Prior chemotherapy was limited to one regimen. Trastuzumab was administered weekly (loading dose of 4 mg/kg i.v. and 2 mg/kg thereafter). Irinotecan 125 mg/m2, i.v. was administered weekly for 4 weeks with a 2-week rest period. RESULTS: HER-2/neu overexpression was detected in 11 of 138 (8.0%) of screened tumors (2+ in 5 and 3+ in 6 patients). Nine patients were entered in the study; 6 had received prior chemotherapy. Partial responses were seen in 5 of 7 evaluable patients. Grade 3-4 toxicities in 31 cycles of therapy included diarrhea (19%), nausea (10%), and vomiting (6%). Leukopenia occurred in 6%, and congestive heart failure and acute renal failure (secondary to diarrhea and dehydration) were seen in 3% of cycles. The study was prematurely closed due to low accrual. CONCLUSIONS: The low overexpression rate of HER-2/neu (8.0%) in advanced CRC limits the potential for further investigation of regimens involving trastuzumab, despite evidence suggestive of activity. Irinotecan did not alter the pharmacokinetic disposition of trastuzumab.

Adult↗

PubMed2004

Molecular genotyping of medullary thyroid carcinoma can predict tumor recurrence.

Medullary thyroid carcinoma can have an aggressive behavior, and little is known about the molecular basis for clinical outcome. Defining risk of recurrent or metastatic disease is difficult, and it has been limited to clinical and pathologic features, such as advanced age, cervical lymph node metastases, and stage at presentation. Using microdissection and genotyping, we studied 11 cases of medullary carcinoma for allelic losses in a panel of known tumor suppressor genes. The tumor suppressor genes with the most frequent allelic losses were NF2, l-myc, and p53 (75%, 44%, and 44%, respectively). The average frequency of allelic loss across all tumors was 44% and was higher in tumors that recurred. A combination of previously described high-risk variables (increased patient age and cervical lymph node metastases) with the frequency of allelic loss yielded a high-risk group, in which 6 of 6 patients recurred, and a low-risk group, in which 0 of 5 patients recurred (P = 0.004). Frequency of allelic loss in tumor suppressor genes may provide a useful adjunctive prognostic test in medullary thyroid carcinoma.

Adolescent↗

PubMed2004

Tumor suppressor gene allelic loss profiles of the variants of papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTCa) is a relatively common, indolent tumor that usually has an excellent prognosis. While the diagnosis of conventional PTCa is relatively straightforward, encapsulated tumors with follicular growth pattern and unusual or incomplete cytologic features of papillary carcinoma can be diagnostically challenging. Encapsulated, noninvasive tumors are particularly controversial as the differential diagnosis includes a nonneoplastic nodule, a benign follicular adenoma, and papillary carcinoma. In this study, we performed molecular genotyping to identify loss of heterozygosity of tumor suppressor genes in conventional PTCa and in several different morphologic variants, including follicular variant, tall cell variant, and oncocytic variant. Our data demonstrate that conventional PTCas have the lowest frequency of allelic loss (7%), as compared with follicular, oncocytic, and tall cell variants (19%, 34%, and 20%, respectively). Frequency of allelic loss increased with increasing size of the tumors, but did not correlate with age, gender, extrathyroidal extension, or lymph node metastases. Though it is unlikely that these results will enable the distinction between different variants of papillary carcinoma, the finding of significant rates ofallelic loss in the variants of PTCa provides additional evidence of malignancy and may be useful in distinguishing encapsulated tumors from nonneoplastic or benign nodules.

Adult↗

PubMed2004

Correlates of quantitative measurement of BK polyomavirus (BKV) DNA with clinical course of BKV infection in renal transplant patients.

BK virus-allograft nephropathy (BKVAN) is an increasingly recognized complication after kidney transplantation. Quantitative tests have been advocated to monitor patients, but data demonstrating their efficacy are relatively limited. We developed a real-time PCR assay to quantitate BK virus loads in the setting of renal transplantation, and we correlated the BK virus load with clinical course and with the presence of BK virus in renal biopsy specimens. BK virus loads were measured in urine, plasma, and kidney biopsy samples in three clinical settings: (i) patients with asymptomatic BK viruria, (ii) patients with active BKVAN, and (iii) patients with resolved BKVAN. Active BKVAN was associated with BK viremia greater than 5 x 103 copies/ml and with BK viruria greater than 107 copies/ml in all cases. Resolution of nephropathy led to resolution of viremia, decreased viruria levels, and disappearance of viral inclusions, but low-level viral DNA persisted in biopsy specimens even for patients whose viruria was cleared. All but one patient in the resolved BKVAN group carried a urinary viral load below 107 copies/ml. Viral loads in patients with asymptomatic viruria were generally lower but in some cases overlapped with levels more typical of BKVAN. One patient with asymptomatic viruria and with a viral load overlapping values seen in BKVAN had developed nephropathy by the time of follow-up. In conclusion, serial measurement of viral loads by quantitative PCR is a useful tool in monitoring the course of BK virus infection. The results should be interpreted in conjunction with the clinical picture and biopsy findings.

BK Virus↗

PubMed2004

Loss of heterozygosity analysis of benign, atypical, and anaplastic meningiomas.

OBJECTIVE: Up to 70% of typical meningiomas demonstrate allelic loss at chromosome 22q. Allelic loss at additional chromosomal loci is associated with atypia and anaplasia in meningiomas. The pattern of allelic loss or loss of heterozygosity (LOH) follows a nonrandom, multistep pattern. METHODS: All surgical meningioma samples obtained from 1991 to 1992 at the University of Pittsburgh Medical Center were analyzed according to current World Health Organization criteria. Samples without constitutional deoxyribonucleic acid (DNA) were excluded from this analysis. Individual hematoxylin and eosin slides from 43 patients were microdissected, and the DNA was harvested and amplified in the presence of 24 pairs of polymerase chain reaction primers, representing 24 microsatellite loci. The polymerase chain reaction products were subjected to capillary gel electrophoresis and a fluorescence-based DNA analysis system. LOH was defined as ratios of allelic peak heights falling within a conservative threshold of less than 0.5 or more than 2.0. Fisher's exact test and receiver operator characteristic curves were used to test the relationship between benign versus atypical and malignant pathological features and LOH at specific loci or combinations of loci. RESULTS: On review by two independent pathologists, 34 benign meningiomas, 6 atypical meningiomas, and 3 anaplastic meningiomas were identified. The mean number of alleles with LOH was 1.5 +/- 1.2 for benign meningiomas, 6.7 +/- 2.7 for atypical meningiomas, and 8.3 +/- 2.3 for anaplastic meningiomas (P < 0.001). The most important individual loci to predict malignancy were D1S407 (P = 0.006), L-myc (P < 0.001), D10S520 (P = 0.003), D10S1173 (P = 0.042), D11S1920 (P < 0.001), D14S555 (P = 0.041), D17S1289 (P < 0.001), D22S417 (P = 0.001), D22S431 (P = 0.019), and D22S532 (P = 0.028). Combining the LOH data across loci, the area under the receiver operator characteristic curve was 0.993, corresponding to virtually perfect prediction of pathological characteristics. CONCLUSION: Microsatellite marker analysis of allelic loss is a useful method of predicting atypia and anaplasia in meningiomas. More regions of allelic loss are seen in anaplastic and atypical meningiomas as compared with benign meningiomas. This study confirms previously reported chromosomal regions of allelic loss in atypical and anaplastic meningiomas and suggests additional chromosomal regions that may represent heretofore uncharacterized deletions within meningiomas. This type of genetic fingerprint ultimately may serve both a diagnostic and therapeutic role.

Alleles↗

PubMed2004

Molecular analysis to demonstrate that odontogenic keratocysts are neoplastic.

CONTEXT: Odontogenic keratocysts (OKCs) are unique odontogenic lesions that have the potential to behave aggressively, that can recur, and that can be associated with the nevoid basal cell carcinoma syndrome. Whether they are developmental or neoplastic continues to be debated. OBJECTIVES: To identify loss of heterozygosity of tumor suppressor genes in OKCs and to suggest a pathogenetic origin for these lesions. DESIGN: We examined 10 OKCs for loss of heterozygosity of tumor suppressor genes, using a microdissection and semiquantitative genotyping analysis. The genes analyzed included 10 common tumor suppressor genes, as well as the PTCH gene, which is mutated in nevoid basal cell carcinoma syndrome. RESULTS: Loss of heterozygosity was seen in 7 of 10 cases, with a frequency between 11% and 80% of the genes studied. The genes that exhibited the most frequent allelic losses were p16, p53, PTCH, and MCC (75%, 66%, 60%, and 60%, respectively). Daughter cysts were associated with a higher frequency of allelic loss (P =.02), but epithelial budding was not. CONCLUSIONS: Our study indicates that a significant number of OKCs show clonal loss of heterozygosity of common tumor suppressor genes. The finding of clonal deletion mutations of genomic DNA in these cysts supports the hypothesis that they are neoplastic rather than developmental in origin.

Adolescent↗

PubMed2003

Overexpression of the human inducible nitric oxide synthase gene enhances radiation-induced apoptosis in colorectal cancer cells via a caspase-dependent mechanism.

Nitric oxide (NO) has been reported to sensitize cancer cells to radiation. Since delivery of NO to tumors is limited in vivo by systemic toxicity of NO, we examined the potential of gene delivery of the human inducible nitric oxide synthase (iNOS) gene as a means of achieving high output NO production. We successfully transduced two colorectal cancer cell lines as evidenced by increased iNOS protein accumulation and nitrite production. We found that overexpression of iNOS enhanced the effects of radiation on apoptosis in both cell lines in a caspase-dependent fashion. Gene transfer of iNOS holds much promise as a potential radiosensitizer of cancer cells since it increases apoptosis in an additive manner with radiation.

Amino Acid Chloromethyl Ketones↗