Biomedical subjects

K W Gilchrist

Publications and source records attributed to K W Gilchrist.

At least 19 recordsLinked to original sources

PubMed2000

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P </=.01). Within the first 5 years of follow-up, mitotic index (P =.004), grade (P =.004), ploidy (P =. 006), and SPF (P =.05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P =.002) in regression models that included other standard prognostic factors. CONCLUSION: A subset of axillary lymph node-positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.

Adult↗

PubMed1998

Overcoming cellular senescence in human cancer pathogenesis.

Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.

Adult↗

PubMed1997

The role of radiotherapy in the management of operable locally advanced breast carcinoma: results of a randomized trial by the Eastern Cooperative Oncology Group.

BACKGROUND: The purpose of this study was to test the role of radiotherapy following total mastectomy, axillary dissection, and adjuvant systemic therapy in the management of operable locally advanced breast carcinoma. METHODS: After undergoing mastectomy and axillary dissection, 426 patients with locally advanced breast carcinoma were registered on study and stratified by patient characteristics and risk factors. All patients were then treated with six courses of chemohormonotherapy. After being restaged, the 332 patients remaining without recurrence were randomized to receive prophylactic radiotherapy or to undergo observation and receive radiotherapy only if and when there was locoregional recurrence. RESULTS: Three hundred twelve of 332 randomized patients were deemed eligible and analyzed for both time to relapse and survival. The median follow-up period was 9.1 years. There were no significant differences in time to relapse and overall survival between the two treatment arms. Of those assigned to radiation, 60% relapsed, with a median time to relapse of 4.7 years, and 46% were alive at last follow-up, with a median survival of 8.3 years. Of those assigned to observation, 56% relapsed, with a median time to relapse of 5.2 years, and 47% were alive at last follow-up, with a median survival of 8.1 years. The two treatment arms had significantly different patterns of sites of first recurrence. There were 9% fewer locoregional first recurrences among those assigned to radiation than among those assigned to observation (15% vs. 24%), whereas there were 15% more first relapses at distant sites (50% vs. 35%) among those assigned to radiation (P = 0.003). CONCLUSIONS: Radiotherapy for locally advanced breast carcinoma, following mastectomy, axillary dissection, and adjuvant systemic therapy, results in fewer locoregional but more distant recurrences at first relapse. No significant advantage was seen for consolidation radiotherapy over observation in terms of either time to relapse or survival, both of which were virtually identical in the two treatment arms. [See editorial counterpoint on pages 1061-6 and reply to counterpoint on pages 1067-8, this issue.]

Adult↗

PubMed1996

Lack of association between tumor necrosis and hsp-27 expression in primary breast cancer.

Overexpression of heat shock protein 27 (hsp-27) is associated with reduced disease-free survival in early stage breast cancer. Histopathologic evidence of confluent necrosis within primary infiltrating ductal carcinoma (IDC) is similarly an indication of poor prognosis. We postulated that IDC evidencing confluent tumor necrosis (TN) might overexpress this protein, which would help explain why hsp-27 is associated with higher-risk cancers. To test this hypothesis, presence of TN (as opposed to individual cell apoptosis) and of hsp-27 expression by immunohistochemistry were evaluated independently in 48 specimens of IDC. Nineteen (40%) overexpressed hsp-27 and 10 (21%) displayed necrosis. IDCs with areas of TN are less likely to overexpress hsp-27, suggesting a lack of association between these histoprognostic variables. This negative correlation, however, supports hsp-27 as an independent predictor of high-risk disease.

Apoptosis↗

PubMed1996

FISH detection of HER-2/neu oncogene amplification in early onset breast cancer.

HER-2/neu (c-erbB-2) gene amplification based on Southern blotting or immunohistochemistry has been shown to be predictive of poor outcome in breast cancer occurring in women over 40, but there is little data on the role of HER-2/neu in young women with breast cancer, many of whom may have inherited BRCA1 or other predisposing genes. The present study used fluorescent in situ hybridization (FISH) on archival specimens of breast cancer from 37 women under the age of 40 to evaluate the role of HER-2/neu amplification in this cohort, and to also evaluate the efficacy of FISH for quantifying amplification. The frequency of primary tumors with a greater than fourfold increase in gene copy number was found to be 38%, which is similar to the frequency of amplification reported in Southern blot studies in older women. However, the greater sensitivity of FISH enabled detection of low level amplification (more than 2 but less than 8 gene copies), which was found in an additional 30% of the tumors. Patients with low level amplification demonstrated a 54% recurrence rate, compared to 86% in those with high amplification and 17% in those with no amplification. HER-2/neu amplification appeared to be more prognostic of recurrence than nodal status, with 45% of node negative tumors recurring compared to 62% of those which were node positive, nor was tumor size predictive of recurrence in this cohort since tumors of 2 cm or less recurred in 44% of cases compared to 57% of those larger than 2 cm. Thus, this study demonstrates that FISH is a reproducible and sensitive technique for detecting HER-2/neu amplification, and that amplification of the oncogene is the strongest independent indicator of recurrence of breast cancer in young women.

Adult↗

PubMed1996

Heat shock protein 27 overexpression in breast cancer lymph node metastasis.

BACKGROUND: Heat shock protein 27 (hsp-27) is overexpressed in approximately 67% pure ductal carcinoma in situ (DCIS), in approximately 50% DCIS associated with invasive ductal carcinoma (IDC), and in approximately 25% IDC alone. If this decrease in hsp-27 expression has a role in the progression of malignancy in IDC, we postulate a further reduction in expression in nodal metastasis. METHODS: To test this hypothesis, we evaluated the distribution of hsp-27 in primary IDC and in synchronous regional lymph node metastasis within the same patient by immuno-histochemistry. RESULTS: Nine of 30 primary IDCs (30%) and 22 of 30 lymph node metastases (73%) overexpressed hsp-27. Contrary to our hypothesis, of 21 IDCs with no or low hsp-27 expression, 13 (62%) had overexpression of this protein within nodal metastasis. CONCLUSIONS: hsp-27 appears to confer cytoprotection for metastatic cells, which may help explain why hsp-27 overexpression is associated with reduced disease-free survival in breast carcinomas.

Breast Neoplasms↗

PubMed1996

Sulcus vocalis: a rational analytical approach to diagnosis and management.

The term sulcus vocalis has been applied to a spectrum of disorders ranging from minor vocal fold indentations to destructive lesions causing severe dysphonia. To clarify the pathophysiology and to develop a more rational approach to treatment, we report a series of sulcus patients including 20 surgical cases. Clinical and histopathologic analysis produced a clinically useful classification: type 1 is a physiologic variant accentuated by atrophy but with intact lamina propria; types 2 (sulcus vergeture) and 3 (sulcus vocalis) are characterized by severe dysphonia, loss of vibratory activity, and destruction of the functional superficial lamina propria. These latter cases respond favorably to microsurgery designed to remove destroyed tissue, release scar contracture, and promote mucosal redraping by regional undermining. Further study of the extracellular matrix of the superficial lamina propria (Reinke's space) might indicate a common pathway in the pathogenesis of sulcus deformities and other related benign vocal fold lesions.

Adult↗

PubMed1995

Abnormal rectal mucosa of the anal transitional zone in ulcerative colitis.

OBJECTIVE: To determine the frequency of atypia and active ulcerative colitis (UC) in rectal mucosa within the anal transitional zone (ATZ). DESIGN: Surgeons identified ATZ tissues from restorative proctocolectomy specimens for determination by surgical pathologists of specific histopathologic features in rectal mucosa of the ATZ. SETTING: Surgical referral center for restorative proctocolectomy. PATIENTS: Ninety-four patients with symptomatic UC underwent restorative proctocolectomy between January 1991 and December 1994. INTERVENTIONS: Specific histopathologic features of active UC in the ATZ were evaluated by a single reviewer who did not know the clinicopathologic details of individual study patients. MAIN OUTCOME MEASUREMENTS: Presence and coexistence of rectal mucosal dysplasia (high or low grade), mucosa classified as indefinite for dysplasia, and acute UC (crypt abscess or cryptitis) in the ATZ. RESULTS: Of 94 ATZ tissue specimens, acute intracryptic inflammation was present in 60 rectal mucosa specimens (64%). In 29 (48%) of these 60 specimens, inflammation was neither widespread nor intense. Rectal mucosal dysplasia (low grade but not high grade) was present in 15 (16%) of 94 ATZs specimens. Inflammation elsewhere in the rectal mucosa accompanied dysplasia in 11 (73%) of 15 ATZ specimens. Rectal mucosa classified as indefinite for dysplasia was present in 24 (26%) of 94 ATZ specimens and coexisted with inflammation in 15 (63%) of these 24. Thus, rectal mucosal atypia was present in 39 (41%) of 94 ATZ specimens, and in 26 (67%) of these 39, abnormal rectal mucosa coexisted with acute inflammation. CONCLUSIONS: Rectal mucosa in the ATZ can exhibit active UC and/or atypia. Long-term monitoring is advisable if the ATZ is preserved during restorative proctocolectomy.

Colitis, Ulcerative↗

PubMed1995

Distribution of Hsp-27 and HER-2/neu in in situ and invasive ductal breast carcinomas.

BACKGROUND: The overexpression of heat shock protein 27 (hsp-27) in early-stage breast cancer is associated with histopathologic features of poor prognosis and clinically with an increased probability of disease recurrence. Hsp-27 is overexpressed in 25% of invasive ductal carcinomas (IDC); however, its distribution in ductal carcinoma in situ (DCIS) and DCIS associated with IDC has not been investigated. We postulated that hsp-27 might be detected and variably expressed in DCIS and, like HER-2/neu oncoprotein expression, might be a tumor-specific marker worthy of future clinical investigation. METHODS: To test these hypotheses, the distribution of hsp-27 in noncomedo and comedo DCIS, and DCIS associated with IDC, was evaluated by immunohistochemistry and compared with HER-2/neu expression within the same cancers. RESULTS: Hsp-27 was overexpressed in 28 of 47 (approximately 60%) cases of DCIS; expression in pure DCIS was 16 of 24 (67%), and 12 of 23 (approximately 50%) in DCIS associated with IDC. Hsp-27 expression by in situ and invasive components of the same neoplasm were concordant in 22 of 23 (approximately 95%) cases tested. Comedo variants appeared to have somewhat higher hsp-27 expression than noncomedo DCIS, whether or not there was an associated IDC. These results are reminiscent of HER-2/neu oncoprotein expression in DCIS and DCIS associated with IDC observed by others. However, although 4 of 22 (18%) cancers containing DCIS + IDC expressed HER-2/neu, no relationship with hsp-27 expression in the same cancers was observed. CONCLUSIONS: We found a high incidence of hsp-27 overexpression in DCIS and in DCIS associated with IDC. This rate is twice that previously observed in IDC alone. Hsp-27 expression is independent of HER-2/neu expression.

Adult↗

PubMed1995

Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations.

OBJECTIVES: Because repetitive hematuria home screening with a chemical reagent strip can detect early stage bladder cancer (BC) in asymptomatic middle-aged and elderly men, the ability of this screening to effect earlier detection and reduce BC mortality was investigated. METHODS: Grades, stages, and outcomes of BCs detected by hematuria screening in 1575 men were compared with those of all newly diagnosed BCs in men age 50 years or older reported to the Wisconsin cancer registry in 1988. BC grades and stages were assigned by review of all pathology slides/blocks, and causes of deaths were determined from cancer registry records. As an additional control group, outcomes of BC cases diagnosed in men solicited to take part in screening, who declined, were also determined. RESULTS: The proportions of low-grade (grades 1 and 2) superficial (Stages Ta and T1) versus high-grade (grade 3) or invasive (Stage T2 or higher) cancers in cases detected by hematuria screening (screened cases) and those reported to the tumor registry (unscreened cases) were not significantly different (52.4% versus 47.7% in 21 screened and 56.8% versus 43.3% in 511 unscreened cases) (P > 0.20). Of the high-grade or invasive cases, however, the proportion of late stage (T2 or higher) tumors was significantly lower in the screening-detected BCs compared to unscreened ones (P = 0.007). No screened case has died of BC (3- to 9-year follow-up), whereas 16.4% of unscreened cases have within 2 years of diagnosis (P = 0.025). Twenty-three of 1940 (1.2%) men who were solicited but chose not to participate in screening were diagnosed with BC within 18 months after what would have been their last home screening date, compared with 1.3% of participants having BC detected by screening. Thus, screening participants and those who were solicited and declined had similar likelihoods of developing BC. CONCLUSIONS: Hematuria home screening detects high-grade cancers before they become muscle invading and significantly reduces BC mortality.

Aged↗

PubMed1994

Tumor cell kinetics using two labels and flow cytometry.

A flow cytometry based, single sampling method employing sequential bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) labeling with an intervening interval is examined. BrdUrd-specific and nonspecific monoclonal antibodies and flow cytometry are used to estimate the duration of DNA synthesis and the potential doubling time in tumor cell populations using a single sampling or biopsy. A correction for labeled, divided cells allows postlabel incubation intervals to exceed the length of the G2/M phase of the cell cycle. The method yields reliable results when tested in experimental tumor systems in vitro and in situ, as well as in nine human tumors labeled in situ. It uses a somewhat simpler analysis than the alternative relative movement method, requiring only labeling indices, rather than both a labeling index and relative movement, but doses require the administration of two, rather than one, label. It provides an independent verification of and a useful single sampling alternative to the relative movement method for the estimation of the length of S phase and, from this, the potential doubling time in experimental or clinical human tumors.

Animals↗

PubMed1994

In vitro radiation-induced neoplastic progression of low-grade uroepithelial tumors.

Recent interest has focused on the identification of molecular genetic mechanisms in multistep neoplastic transformation. In vitro exposure of simian virus 40 (SV40)-immortalized human uroepithelial cells (SV-HUC) that are environmentally relevant to bladder carcinogens has been shown to produce tumorigenic transformation, as assessed by the ability of cells exposed to a carcinogen to form xenograph tumors with heterogeneous cancer phenotypes ranging from very aggressive, invasive high-grade carcinomas to superficial low-grade indolent tumors. In addition, exposure of a low-grade indolent tumor generated in the SV-HUC system, MC-T11, to the same carcinogens results in neoplastic progression as assessed by the production of high-grade aggressive cancers. In the present study, we show neoplastic progression of MC-T11 after in vitro exposure to a single dose of 6 Gy X rays. In addition, we show that the chromosome deletions, including losses of 4q, 11p, 13q and 18, observed in these radiation-induced tumors are similar to those observed in carcinogen-induced tumors, thus supporting the hypothesis that the experimental cell system, not the transforming agent, dictates the genetic losses required for tumorigenic transformation and progression.

Animals↗

PubMed1993

High DNA content and prognosis in lymph node positive breast cancer. A case control study by the University of Leiden and ECOG. (Eastern Cooperative Oncology Group).

To investigate whether breast cancer cells with unusually high nuclear DNA content are associated with an adverse outcome, Eastern Cooperative Oncology Group investigators selected breast cancer trial patients who suffered an early death (ED) within two years after diagnosis to compare with other trial patients who had a survival of at least 7.5 years. Paraffin blocks of primary breast cancers were obtained from 93 evaluable patients who had been enrolled in two surgical adjuvant trials for lymph node positive (LN+) disease (T1-3N1M0). Single cell monolayer preparations from these blocks were stained with acriflavine-Feulgen and analyzed by image analysis for DNA content with the automated Leiden Television Analysis System (LEY-TAS). Standard prognostic variables (estrogen receptor (ER) status, number of lymph nodes with metastases, and size of the cancer) were compared with three DNA content characteristics: DNA ploidy status, number of nuclei with > 5C DNA content, and percent of nuclei with > 5 C. Estimates of the odds ratio in multivariate comparisons showed that ER negativity was associated with ED (p = 0.0005) and an odds ratio estimate using negative/positive of 4.87. The number of positive lymph nodes associated with ED had a p-value of 0.0005 and an odds ratio estimate of 4.63 when comparing the > 3 nodes group to the 1-3 nodes group. In contrast, the strongest association for any of the DNA content characteristics with ED had a p-value of 0.017 and an odds ratio estimate of 2.76. This power of association disappeared when stratified on ER status.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1993

Hsp-27 has no diagnostic or prognostic significance in prostate or bladder cancers.

Heat shock protein 27 (hsp-27) is a cytosol protein of unknown function that is concentrated in many estrogen-sensitive normal target organs and is expressed to a varying degree in many tumors, including ductal carcinoma of the breast, malignant fibrous histiocytoma (MFH) of the soft tissues, adenocarcinoma of the prostate, and transitional cell carcinoma (TCC) of the urinary bladder. Overexpression of hsp-27 has independent prognostic significance in patients with breast cancer and MFH, but its potential predictive value with prostate and bladder cancers has not been evaluated. Differential expression of hsp-27 may occur between invasive cancer and host tissue that could aid in diagnosis, and varying expression among invasive cancers may have potential prognostic significance that could influence the use of adjuvant therapy. To test these hypotheses, hsp-27 expression was evaluated by immunohistochemistry in archival formalin-fixed paraffin-embedded sections of primary prostate and bladder carcinomas where the outcome of the patient was known. In 36 prostate cancer specimens from patients who had undergone radical prostatectomy (Stages T1, T2; N0; M0), no normal glandular elements or invasive cancers expressed this protein. In 24 bladder cancer specimens from patients who had undergone radical cystectomy (Stages T2, T3A, T3B, T4A; N0, N1; M0), 12 (50%) cancers overexpressed this protein. Hsp-27 did not correlate with degree of histologic differentiation, T-stage, nodal status, local recurrence, metastases, or survival. From these observations, we conclude that hsp-27 expression has neither diagnostic nor prognostic significance and will not serve as a predictive biologic marker with these important genitourinary cancers.

Adenocarcinoma↗

PubMed1993

Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients.

PURPOSE: The Eastern Cooperative Oncology Group (ECOG) entered 766 patients onto two prospectively randomized surgical adjuvant clinical trials for lymph node-positive breast cancer (T1-3N1M0). Ninety-five percent (n = 728) of eligible patients have complete information on the prognostic covariables under study (tumor necrosis [TN], tumor size, number of positive lymph nodes, age) and a median follow-up duration of 10.3 years. METHODS: TN was defined as confluent cell death in invasive areas of primary cancers, visible at 4 x objective lens magnification. Cox proportional hazards models were used to estimate presence versus absence of TN effects on clinical outcomes over full cross-stratification of variables, including delivery of chemotherapy versus observation only. Time-varying effects were modeled using spline functions of time, and by fixing proportional hazards models separately in the time periods 0 to 2 and 2+ years. RESULTS: Presence of TN was an independent predictor for time to recurrence (TTR) (P = .007) and for survival (P = .0003) in the overall 10-year follow-up period. Presence of TN was also an independent predictor for TTR and for survival (each P < .0001) in the period 0 to 2 years after diagnosis. Spline function time-modeling calculations showed different hazard ratios in the TN-present (TN+) versus TN-absent (TN-) groups for both TTR and survival (each P < .0001). This difference is changing over time (P = .0001 for TTR, P = .0005 for survival). Once a patient has been disease-free beyond 2 years after diagnosis, presence or absence of TN is irrelevant to future prognosis. CONCLUSION: Confluent TN of any dimension in invasive areas of lymph node-positive breast cancer is an independent predictor for early recurrence and death from the disease.

Breast Neoplasms↗

PubMed1993

Esthesioneuroblastoma: diagnosis, prognosis, and treatment.

Esthesioneuroblastoma is a rare neoplasm arising from the olfactory epithelium and characterized by slow growth, frequent local recurrence, and metastasis. This tumor has no known etiologic cause and has been studied from clinically retrospective analysis. The historic treatment of esthesioneuroblastoma has included surgical resection, adjuvant radiation therapy, and chemotherapy for advanced disease. We describe a case of esthesioneuroblastoma which illustrates the diagnostic, prognostic, and therapeutic aspects of this uncommon neoplasm.

Aged↗

PubMed1992

Age as a predictor of an aggressive clinical course for superficial bladder cancer in men.

Tumor grade and stage are two of the strongest predictors for indolent versus aggressive clinical course in bladder cancer. To identify age-related trends in tumor aggressiveness the authors investigated the relationships of age with grade and stage. Pathologic specimens were obtained for 89% (527 of 590) of new bladder cancer cases among men older than 50 years of age reported to the state tumor registry in Wisconsin for 1988. Tumors were grouped as low grade (G1, G2) or high grade (G3), and as superficial (Ta) or invasive (greater than or equal to T1), according to the TNM system. This analysis included 485 transitional cell carcinomas (TCC) for which the authors determined stage-stratified and grade-stratified odds ratios for men 50 through 64 years of age and older than 65 years of age. Men older than 65 years of age with superficial TCC were more than three times as likely to have a high-grade malignancy than men 50 through 64 years of age (P = 0.01); the odds ratio was 3.44 (95% CI = 1.28, 9.26). A relationship was not apparent for invasive TCC. Age and stage were weakly associated for low-grade and high-grade TCC that may be due, in part, to the strong correlation of stage with grade as a prognostic indicator. These data suggest that men in older age groups are at increased risk for superficial bladder cancer of high grade, which portends an aggressive clinical course.

Age Factors↗

PubMed1992

Tumorigenic transformation and neoplastic progression of human uroepithelial cells after exposure in vitro to 4-aminobiphenyl or its metabolites.

A multistep in vitro/in vivo transformation system was used to test the transforming effect(s) of the human bladder procarcinogen 4-amino-biphenyl (ABP) and two putative proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP) and N-hydroxy-4-acetylamino-biphenyl (N-OH-AABP), on a clonally derived nontumorigenic SV40-immortalized human uroepithelial cell line, SV-HUC. SV-HUC were exposed in vitro to concentrations of ABP, N-OH-ABP, or N-OH-AABP that caused a range of cytotoxicity from 5 to 76%. Tumorigenic transformation of SV-HUC, as assessed by the ability of the exposed cells to form carcinomas when inoculated s.c. into athymic nude mice, was achieved after a single exposure to ABP, N-OH-ABP, or N-OH-AABP. In the tumorigenic transformation experiments, 28 of 45 mice representing all 15 carcinogen-exposed observation groups formed carcinomas, whereas none of 9 mice from control groups formed carcinomas (P = 0.001). Neoplastic progression of a low grade regressive squamous cell carcinoma, MC-T11, was also achieved in this system after in vitro exposure to ABP, N-OH-ABP, or N-OH-AABP. In these progression experiments, 11 of 33 mice representing 7 of 12 carcinogen-exposed observation groups formed persistent, high grade nongressing tumors, while only 1 of 19 untreated MC-T11 controls spontaneously progressed on reinoculation (P = 0.022). Forty independent carcinomas generated in athymic nude mice recapitulated diverse cancer phenotypes (including different growth kinetics and histopathological subtypes and grades) represented in clinical bladder cancers. These results demonstrate for the first time the transforming effects of the potent human carcinogen ABP and two of its proximate N-hydroxy metabolites on a prime human target cell type, HUC.

Aminobiphenyl Compounds↗