Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/Detect™ versus Veridex CellSearch™ system.

The detection of CTCs prior to and during therapy is an independent and strong prognostic marker, and it is predictive of poor treatment outcome. A major challenge is that different technologies are available for isolation and characterization of CTCs in peripheral blood (PB). We compare the CellSearch system and AdnaTest BreastCancer Select/Detect, to evaluate the extent that these assays differ in their ability to detect CTCs in the PB of MBC patients. CTCs in 7.5 ml of PB were isolated and enumerated using the CellSearch, before new treatment. Two cutoff values of ≥2 and ≥5 CTCs/7.5 ml were used. AdnaTest requires 5 ml of PB to detect gene transcripts of tumor markers (GA733-2, MUC-1, and HER2) by RT-PCR. AdnaTest was scored positive if ≥1 of the transcript PCR products for the 3 markers were detected at a concentration ≥0.15 ng/µl. A total of 55 MBC patients were enrolled. 26 (47%) patients were positive for CTCs by the CellSearch (≥2 cutoff), while 20 (36%) were positive (≥5 cutoff). AdnaTest was positive in 29 (53%) with the individual markers being positive in 18% (GA733-2), 44% (MUC-1), and 35% (HER2). Overall positive agreement was 73% for CTC≥2 and 69% for CTC≥5. These preliminary data suggest that the AdnaTest has equivalent sensitivity to that of the CellSearch system in detecting 2 or more CTCs. While there is concordance between these 2 methods, the AdnaTest complements the CellSearch system by improving the overall CTC detection rate and permitting the assessment of genomic markers in CTCs.

Technical validation of an autoantibody test for lung cancer.

BACKGROUND: Publications on autoantibodies to tumour-associated antigens (TAAs) have failed to show either calibration or reproducibility data. The validation of a panel of six TAAs to which autoantibodies have been described is reported here. MATERIALS AND METHODS: Three separate groups of patients with newly diagnosed lung cancer were identified, along with control individuals, and their samples used to validate an enzyme-linked immunosorbant assay. Precision, linearity, assay reproducibility and antigen batch reproducibility were all assessed. RESULTS: For between-replicate error, samples with higher signals gave coefficients of variation (CVs) in the range 7%-15%. CVs for between-plate variation were only 1%-2% higher. For between-run error, CVs were in the range 15%-28%. In linearity studies, the slope was close to 1.0 and correlation coefficient values were generally >0.8. The sensitivity and specificity of individual batches of antigen varied slightly between groups of patients; however, the sensitivity and specificity of the panel of antigens as a whole remained constant. The validity of the calibration system was demonstrated. CONCLUSIONS: A calibrated six-panel assay of TAAs has been validated for identifying nearly 40% of primary lung cancers via a peripheral blood test. Levels of reproducibility, precision and linearity would be acceptable for an assay used in a regulated clinical setting.

Five-year stability study of free and total prostate-specific antigen concentrations in serum specimens collected and stored at -70 degrees C or less.

The stability of total (t) and free (f) prostate-specific antigen (PSA) in male serum specimens stored at -70 degrees C or lower temperature for 4.7 to 4.9 years was studied. Until now, the stability of these analytes in serum has not been evaluated systematically beyond 2 years of storage at -70 degrees C. Aliquots of frozen serum were thawed in 2001 and 2006 and assayed for tPSA and fPSA using a Dade Behring Dimension(R) RxL analyzer and reagents. tPSA values ranged from 0.07 to 69.94 and 0.00 to 69.83 ng/mL in 2001 and 2006, respectively, whereas fPSA values for the tested specimens ranged from 0.02 to 5.72 and 0.00 to 5.92, respectively. Deming regression analyses showed agreement in assay values over time as tPSA values yielded a slope of 1.0112 and a y-intercept of 0.0195; fPSA values produced a slope 1.0538 and a y-intercept of -0.0442; f/tPSA values yielded a slope of 0.9631 and a y-intercept of 0.1195. A Bland-Altman analysis of the data demonstrated analyte and ratio stability over this time period. We conclude that serum, when collected properly and stored at -70 degrees C or lower temperature, may be used for tPSA and fPSA clinical studies for at least 5 years after collection.

Can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total prostate specific antigen between 2.5 and 4.0 ng./ml.

PURPOSE: We assessed whether complexed prostate specific antigen (PSA) and complexed PSA referenced variables would enhance prostate cancer detection in men with serum total PSA between 2.5 and 4.0 ng./ml. MATERIALS AND METHODS: Transition zone and total prostate gland volumes were determined in 151 men who underwent prostate biopsy using an 11 core biopsy strategy. In addition to measuring the Bayer section sign complexed PSA assay, we also calculated 2 computed complexed PSA values (Hybritech parallel total PSA--Hybritech free PSA and Bayer total PSA--Hybritech free PSA). We calculated 8 volume referenced variables using total and complexed PSA, and 2 computed complexed PSA values by dividing each value by the total prostate and transition zone volumes. RESULTS: Of the 151 patients 37 (24.5%) had cancer. In 10 of the 37 men with cancer (27%) a positive core was present in only 1 or more of the 5 alternate regions not sampled by conventional sextant biopsies. At 92% sensitivity a cutoff value of 2.3 ng./ml. for complexed and 31% for free-to-total PSA provided 42% and 11% specificity, respectively (p <0.001). In the 116 men with a total prostate volume of 30 cc or greater at 92% sensitivity the specificity of complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (52%) were better than that of complexed (40%) and free-to-total (11%) PSA. In the 35 men with a total prostate volume of less than 30 cc at 92% sensitivity the specificity of complexed PSA (50%), complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (55%) were significantly better than that of free-to-total PSA (8%, p <0.001). The area under the curve of complexed PSA was almost identical to that of the 2 computed complexed PSA calculations. CONCLUSIONS: A substantial proportion of men with total PSA values between 2.5 and 4.0 ng./ml. had prostate cancer. Complexed and computed complexed PSA were more specific than the free-to-total PSA ratio when total PSA was between 2.5 and 4.0 ng./ml. A 2.3 ng./ml. threshold for complexed and computed complexed PSA appears to stratify prostate biopsy results in men with total PSA between 2.5 and 4.0 ng./ml. The computed complexed PSA calculation appears to be equivalent to the complexed PSA serum assay for detecting cancer. Volume referenced complexed PSA performed better than complexed PSA in men with a total prostate volume of 30 cc or greater compared to men with a total prostate volume of less than 30 cc.

Lactate dehydrogenase isoenzyme 1 is the most important LD isoenzyme in patients with testicular germ cell tumor.

We examined the clinical utility of serum lactate dehydrogenase (LD) isoenzyme catalytic concentrations in 58 patients with testicular germ cell tumors (TGCT) (13 with seminoma and 45 with non-seminomatous tumors). Twenty-one patients with no evidence of disease (NED) all had serum LD isoenzyme 1 catalytic concentrations (LD-1) and LD-1/LD fractions below the upper limit of the reference values (ULR). LD-1 and the LD-1/LD fraction discriminated significantly between evidence of disease (ED) and NED (p = 0.00009 and p = 0.028, respectively, Mann Whitney U-test). Twenty of the 37 patients with ED had raised values of LD-1. The 17 patients with an LD-1 < 1.0 x ULR had a better survival than the 10 patients with LD-1 between 1.0 and 2.9 x ULR, the 7 with LD-1 between 3.0 and 5.9 x ULR, and the 3 patients with LD-1 > 6.0 x ULR (p = 0.006, log-rank test, chi2 test for trend)). Twenty-three patients with an LD-1/LD fraction < or = 0.25 had a better survival than the 14 with an LD-1/LD fraction > 0.25 (p = 0.013). Nineteen patients with LD-5 < 105 U/L and the 15 with LD-5 > 105 U/L had a similar rate of survival (p = 0.85). Our findings add to the evidence showing LD-1 in preference to LD as a serum tumor marker of TGCT.

N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium.

Lung cancer remains the number one cause of cancer-related deaths in the United States. To reduce the mortality associated with this disease, individuals at risk must be identified prior to the development of lung cancer, and effective prevention strategies must be developed. One such strategy is to use retinoids like N-(4-hydroxyphenyl)retinamide (4-HPR), which has been found to possess chemopreventive activities in preclinical studies. In this study, 139 smokers were registered and 82 were randomized onto a double-blinded, placebo-controlled chemoprevention trial of 4-HPR administered p.o. (200 mg once daily). Of these, 70 participants were eligible for response evaluation. Biopsies were obtained at six predetermined sites in the bronchial tree from participants before and at the completion of 6 months of treatment. 4-HPR treatment had no measurable effect on histopathology (squamous metaplasia and dysplasia) in the bronchial epithelium of current smokers. 4-HPR was detected (104.5+/-64.0 ng/ml, mean +/- SD) in the serum of participants, supporting its potential bioavailability. Serum retinol levels decreased markedly (44% of placebo-treated patients) as a consequence of 4-HPR treatment. Notably, the mRNA level of retinoic acid receptor beta, which is typically increased by retinoid treatment, did not change in the bronchial epithelium of 4-HPR-treated participants. Clonal populations of bronchial epithelial cells were detected by analysis of loss of heterozygosity at putative tumor suppressor loci on chromosomes 3p, 9p, and 17p, and these changes were not altered by 4-HPR treatment. In conclusion, at this dose and schedule, 4-HPR was not effective in reversing squamous metaplasia, dysplasia, or genetic and phenotypic abnormalities in the bronchial epithelium of smokers.

Relative contributions of technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism.

HYPOTHESIS: Technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay have been used to permit a directed operation in patients with hyperparathyroidism. We hypothesized that the coordinated use of these techniques might be particularly useful in patients who require a second operation for hyperparathyroidism. DESIGN: Retrospective analysis was performed to determine the specific contribution of these technologies to the surgical management of patients with hyperparathyroidism who underwent evaluation by at least 2 of these techniques between April 1996 and October 1999. SETTING: Patients were evaluated and treated by an endocrine tumor surgery group within a tertiary care referral center. PATIENTS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and/or the rapid parathyroid hormone assay was performed in 32 patients. RESULTS: Twenty-eight of 32 patients had primary hyperparathyroidism, 3 had multiple endocrine neoplasia type 1, and 1 had secondary hyperparathyroidism. The surgical procedure was an initial cervical exploration in 19 and a second operative procedure in 13. Parathyroidectomy was successful in all patients. A directed anatomic operation was performed in 24 patients, including 11 patients who underwent second operative procedures and 9 patients who underwent minimally invasive procedures under local anesthesia. A directed operation was facilitated by sestamibi scan in 22 of 24 patients, intraoperative gamma probe detection in 5 of 23 patients, and the rapid parathyroid hormone assay in 15 of 15 patients. CONCLUSIONS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay allows for successful directed reoperative parathyroidectomy; a minimally invasive procedure may be performed in selected patients.

Urinary nuclear matrix protein 22 (NMP22): a diagnostic adjunct to urine cytologic examination for the detection of recurrent transitional-cell carcinoma of the bladder.

This study compares urine nuclear matrix protein 22 (NMP22) immunoassay and conventional urine cytologic examination for detecting recurrent transitional-cell carcinoma (TCC) of the urinary bladder. One hundred twenty-eight urine specimens from 107 patients with a history of TCC of the urinary bladder were studied. NMP22 immunoassay and conventional cytologic examination were performed on each specimen. The NMP22 and cytology results were then compared with the results of subsequent cystoscopies/surgical biopsies performed over a 6-mo follow-up period. The sensitivity of urine cytologic study for predicting recurrent TCC was 60%, while the sensitivity of NMP22 assay was 47%. When both NMP22 assay results and the cytologic interpretation were positive for TCC, the positive predictive value of the combined tests was 74%. When both tests showed negative results, the negative predictive power was 81%. Our findings suggest that urine NMP22 assay may represent a useful diagnostic adjunct to conventional urine cytologic examination for the detection of recurrent TCC of the urinary bladder.

Calcium-induced activation of a mutant G-protein-coupled receptor causes in vitro transformation of NIH/3T3 cells.

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that is widely expressed, has tissue-specific functions, and regulates cell growth. Activating mutations of this receptor cause autosomal dominant hypocalcemia, a syndrome characterized by hypocalcemia and hypercalciuria. The identification of a family with an activating mutation of the CaR (Thr151Met) in which hypocalcemia cosegregates with several unusual neoplasms led us to examine the transforming effects of this mutant receptor. Transfection of NIH/3T3 cells with the mutant but not the normal receptor supported colony formation in soft agar at subphysiologic calcium concentrations. The mutant CaR causes a calcium-dependent activation of the extracellular signal-regulated protein kinase (ERK) 1/2 and Jun-N-terminal kinase/stress-activated (JNK/ SAPK) pathways, but not P38 MAP kinase. These findings contribute to a growing body of information suggesting that this receptor plays a role in the regulation of cellular proliferation, and that aberrant activation of the mutant receptor in this family may play a role in the unusual neoplastic manifestations.

Evaluation of NMP22 in the detection of transitional cell carcinoma of the bladder.

PURPOSE: Urinary nuclear matrix protein (NMP22) was evaluated for detection of new and recurrent bladder tumors in patients with a history of transitional cell carcinoma. Our objective was to determine sensitivity and specificity of this marker for tumors of various stages and grades, as well as its use as an adjunct to or substitute for urinary cytology. MATERIALS AND METHODS: A total of 231 patients with a history of transitional cell carcinoma provided 288 voided urine samples before cystoscopic examination at 1 of 3 institutions (53 patients were reevaluated at least once). Urine samples were assayed for NMP22 using the NMP22 Test Kit. Select patients underwent biopsy with appropriate additional therapy. Voided urinary cytology was obtained in 200 cases. End points for determination of the absence and presence of tumor were negative cystoscopy and positive biopsy, respectively. A receiver operating characteristics curve was constructed to determine the optimal NMP22 threshold for detection of transitional cell carcinoma. For positive biopsies NMP22 values were also correlated with tumor stage and grade. Comparison to cytology was limited to patients with complete data. RESULTS: There were 208 negative cystoscopies (158 with cytology) and 66 positive cystoscopies with biopsy (42 with cytology). Of the cases 14 were eliminated from statistical analysis due to incomplete data. Receiver operating characteristics curve interpretation determined that 6.4 units per ml. was an optimal reference value for detection of transitional cell carcinoma in this patient group. Sensitivity and specificity for all pathological groupings was 68 and 80%, respectively. When compared to cytology the sensitivities of NMP22 and cytology were 67 versus 31 or 40% (depending on the definition of positive cytology). CONCLUSIONS: NMP22 values represented significant improvement over urinary cytology for detection of transitional cell carcinoma. The sensitivity of NMP22 for detection of transitional cell carcinoma in bladder cancer patients was as much as twice that of cytology when a reference value of 6.4 units per ml. was used. NMP22 analysis was less costly than cytology and operator independent. While NMP22 has previously been shown to be a strong predictor of recurrence after tumor resection, it is an effective and sensitive screening test for detecting tumors in patients with transitional cell carcinoma.

Modulation of cellular proliferation and production of prostate-specific antigen and matrix adhesion molecules in human prostate carcinoma cells by polypeptide growth factors: comparative analyses of MDA PCa2a with established cell lines.

The cellular responses of a newly established and early-passage human prostate adenocarcinoma cell line, MDA PCa2a, to transforming growth factor (TGF) beta1, epidermal growth factor (EGF), and TGFalpha were characterized in terms of proliferation, production of prostate-specific antigen (PSA), fibronectin (FN) and laminin (LM). The responses of the MDA PCa2a cells were compared with those of the well-established human prostate carcinoma cell lines LNCap, PC3, and DU145. The MDA PCa2a cells were more responsive to the growth-inhibitory effect of TGFbeta1 than the established cell lines. The androgen-responsive cell lines (MDA PCa2a and LNCap) were relatively responsive to the growth-stimulatory effect of EGF and TGFalpha whereas the androgen-independent lines (PC3 and DU145) were not. Only the androgen-responsive cells produced PSA, which was further upregulated by treatment with growth factors. The androgen-independent cells did not produce PSA, and growth factors had no effect on PSA production. However, all cell lines produced abundant amounts of FN and LM, and the levels of production of these molecules were subject to modulation by growth factors. It is concluded that each growth factor elicits diverse and distinct responses in prostate carcinoma cells, which may reflect the involvement of diverse post-receptor signal pathways.

Multicenter evaluation of the Bayer Immuno I CA 15-3 assay.

We conducted a multicenter evaluation of the analytical and clinical features of the automated Bayer Immuno 1 CA 15-3 assay and compared assay performance to two manual tests. Results of the 10-day imprecision study of the Bayer Immuno 1 assay pooled across four evaluation sites and three lots of reagent produced total CV < or = 4%. Lot-to-lot reproducibility for 26 different lots of reagents and calibrators manufactured over a 2-year period was demonstrated (CV, 1.1%). Results for the Bayer Immuno 1 assay correlated well with the Biomira TRUQUANT BR 27.29 and Centocor CA 15-3 RIAs (r > or = 0.94). The upper limit of the reference interval for the Bayer Immuno 1 assay was 35.9 kilounits/L (35.9 units/mL); values were similar for all methods. Longitudinal monitoring of healthy women yielded assay values with an average CV of 11% and 21% for the Bayer Immuno 1 and Biomira assays, respectively. The Bayer Immuno 1 assay demonstrated the analytical features, intermethod correlation, and long-term performance characteristics that are essential for longitudinal monitoring of breast cancer patients.

Bayer Immuno 1 PSA Assay: an automated, ultrasensitive method to quantitate total PSA in serum.

The Bayer Immuno 1 PSA Assay measures total PSA in human serum and demonstrates excellent performance with an interassay CV < or = 3.4% and a biological detection limit of 0.03 microgram/L. No significant interference from common hormonal and chemotherapeutic drugs, kallikrein, prostatic acid phosphatase, and trypsin, or elevated levels of total bilirubin, hemoglobin, triglycerides, and IgG was observed. The 95th percentile values for healthy individuals increased with age from 3.0 micrograms/L for males 50-59 years and 3.3 micrograms/L for males 60-69 years, to 4.6 micrograms/L for males > or = 70 years. Clinical studies with retrospective samples demonstrated correspondence between serial measurements of PSA and clinical outcome for 98% of 159 prostate cancer patients. Clinical sensitivity for patients with clinical evidence of disease, untreated at the time of specimen draw, increased with increasing stage from 77.5-100%. Specificity of 60-70% for BPH and other benign urogenital diseases was consistent with previous findings. Bayer Immuno 1 PSA Assay values for 2131 specimens from healthy subjects and patients with prostate cancer, BPH, and other malignant and nonmalignant diseases correlated well with the Abbott IMx PSA Assay over the range 0.0-6,238 micrograms/L (Y = 1.10 x + 0.02). The Bayer Immuno 1 PSA Assay provides automated ultrasensitive, precise, and equimolar measurement of total PSA in human serum.

Evaluation of prostAsure index in the detection of prostate cancer: a preliminary report.

OBJECTIVES: Although prostate-specific antigen (PSA) has revolutionized the detection of prostate cancer, it has definite limitations with respect to its clinical sensitivity and specificity. Because a substantial number (20% to 40%) of men undergoing radical prostatectomy have a PSA level of 4.0 ng/mL or less, any new test offering diagnostic improvement must perform well in patients whose PSA level is less than or equal to 4.0 ng/mL, as well as in patients whose PSA is greater than 4.0 ng/mL. The performances of two tests, the ProstAsure index and the percent free PSA test, were evaluated in detecting cancer. METHODS: We retrospectively analyzed serum samples from 225 men who were grouped into three categories: 94 men who had a normal digital rectal examination and a serum PSA level of 4.0 ng/mL or less, 77 men who were clinically suspected of having benign prostatic hyperplasia (BPH) with a serum PSA level of 4.0 ng/mL or less, and 54 men with localized prostate cancer. The PSA assays were performed using the Hybritech and Tosoh assays and the ProstAsure index was determined by Global Health Net, Savannah, Ga. Receiver operator characteristic (ROC) curves were constructed to evaluate the performance of these two tests, and the areas under the curve were compared for significance. RESULTS: The sensitivity and specificity of detecting prostate cancer using ProstAsure were 93% and 81%, respectively. Using a cutoff value of 15%, the sensitivity and specificity of detecting cancer for percent free PSA were 80% and 74%, respectively (sensitivity increased to 93% and specificity to 59% for free PSA at 19%). In men with a total serum PSA level of 4.0 ng/mL or less, ProstAsure had a lower false-positive rate compared to free PSA level at 19% for men with or without clinical BPH as well as for men without clinical BPH using a 15% free PSA threshold. ProstAsure left fewer cancers undetected (7%) compared to free PSA at the 15% cutoff (20%). CONCLUSIONS: In this study of selected men, ROC curve analysis shows a statistically significant advantage in performance (P = 0.0023) for the ProstAsure index compared to free PSA in detecting prostate cancer.

The effect of 13-cis-retinoic acid chemoprevention on human serum retinol levels.

This study of the effect of 13-cis-retinoic acid on serum levels of retinol was a laboratory correlate of a clinical chemoprevention trial in asymptomatic chronic smokers. All study participants had squamous metaplasia of the bronchial epithelium and received 6 months' treatment of either 13-cis-retinoic acid (1 mg/kg/day) or placebo. Baseline serum retinol levels were compared with levels taken immediately post-treatment. The placebo group (N = 38) had little change, whereas the 13-cis-retinoic acid group, (N = 35) experienced a decline in retinol levels (p = 0.06). Within the 13-cis-retinoic acid group, women's (N = 13) mean serum retinol levels dropped significantly, from 531 +/- 191 ng/ml (baseline) to 436 +/- 115 ng/ml (post-treatment) (p = 0.03); men's (N = 22) levels virtually did not change (p = 0.43). Therefore, the borderline-significant overall decline in the 13-cis-retinoic acid group was due entirely to the decline among women subjects. The etiology of this effect is unknown. Our results suggest that chronic 13-cis-retinoic acid administration may lead to a clinically significant reduction in serum retinol levels in females. This finding may have implications for currently ongoing chemoprevention trials that administer 13-cis-retinoic acid for 3 years.

The induction of benign epithelial neoplasms of the ovaries of guinea pigs by testosterone stimulation: a potential animal model.

We studied the effects of different hormones on the epithelial cells of the ovaries of 11 guinea pigs. Three received testosterone, two received estrone, three megestrol, and three chorionic gonadotropin. Three control guinea pigs received sterile water. Benign epithelial cysts larger than 1.5 mm were found in six guinea pigs, three who received testosterone, one who received megestrol, and two who received chorionic gonadotropin. In one of the three guinea pigs who received testosterone, 2.5-cm bilateral cysts were grossly identified. Papillary excrescences were found on the ovarian surface in four guinea pigs, three who received testosterone and one who received megestrol. The proliferating epithelial cells also formed benign glands in the ovarian stroma in two guinea pigs who received testosterone, the most exuberant epithelial proliferations, including large bilateral cystadenomas, papillary excrescence that formed a small papillary neoplasm, and glands in the ovarian stroma that formed adenomatous areas, were seen in the guinea pig who received an intermediate dose of testosterone for the longest time. By radioimmunoassay, the serum level of testosterone was 22 ng/dL in one of the controls and 10,000, 12,000, and 15,000 ng/dL in the three guinea pigs who received testosterone. In the guinea pig with the most exuberant epithelial proliferation, the level of testosterone in the uterus was similar to that in the serum (13,860 ng/mg), but in the wall of the ovarian epithelial cyst, it was three times higher than it was in the serum (44,000 ng/mg). Our study shows that testosterone stimulates the growth of epithelial cells in the ovaries of guinea pigs, resulting in benign cysts, small adenomas in the ovarian parenchyma, and papillomas on the ovarian surface. The study also shows that guinea pigs can be used as an animal model for epithelial tumors of the human ovary.

A clinical trial to evaluate the effect of vitamin C supplementation on in vitro mutagen sensitivity. The University of Texas M. D. Anderson Clinical Community Oncology Program Network.

Mutagen sensitivity, as measured by an in vitro assay, has been described as a risk factor for the development of several tobacco-related epithelial cancers. In vitro studies have indicated that sensitivity to the clastogenic effects of bleomycin on chromosomes was reduced with the introduction of ascorbic acid in a dose-dependent relationship. We report the results of a randomized clinical trial to determine whether increasing levels of oral ascorbic acid could reduce the levels of mutagen sensitivity. For this study, we recruited 228 healthy smokers from 21 centers around the country through the Clinical Community Oncology Program. Each individual was randomly assigned to one of four daily regimens: placebo, 1 g of ascorbic acid, 2 g of ascorbic acid, or 4 g of ascorbic acid. Treatments were administered for 16 weeks. Assessment of mutagen sensitivity was made at baseline and at weeks 4, 16, and 20 (4 weeks after cessation of treatment). Serum ascorbic acid levels were measured at baseline and at weeks 4 and 16. Demographic and risk factor data were collected at baseline and at each-measurement point. Analyses measured the differences of mutagen sensitivity levels across the four treatment arms, as well as investigating the correlation between serum ascorbic acid level and mutagen sensitivity levels in individuals. We did not find a dose-response relationship between ascorbic acid intake and mutagen sensitivity. Additionally, we did not find an association between serum ascorbic acid levels and mutagen sensitivity.