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Deborah W Knapp

Publications and source records attributed to Deborah W Knapp.

17 recordsLinked to original sources
PubMed2006

Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder.

PURPOSE: The EphA2 receptor tyrosine kinase is believed to play a role in tumor growth and metastasis. The clinical significance of the expression of EphA2 was observed in breast, prostate, colon, skin, cervical, ovarian, and lung cancers. The purpose of this work was to determine the expression of EphA2 and its ligand, Ephrin A-1, and E-cadherin in carcinoma of the urinary bladder, and determine EphA2 as a new target for therapy in bladder cancer. EXPERIMENTAL DESIGN: EphA2 mRNA and protein expression was investigated by reverse transcription-PCR and Western blot, respectively, in bladder cancer cell lines. In addition, the expression of EphA2, Ephrin A-1, and E-cadherin in tissues from patients with different stages of urinary bladder cancer was determined by immunohistochemistry. Furthermore, the ability of Ephrin A-1 to inhibit growth of bladder cancer cells was also investigated using an adenoviral delivery system. RESULTS: Western blot analysis showed high EphA2 expression in TCCSUP, T24, and UMUC-3 cell lines. In tissues, the staining intensity of EphA2 was less in normal urothelium but increased greatly in advancing stages of urothelial carcinoma (P < 0.05). Similarly, the staining intensity of Ephrin A-1 was low in normal tissues and high in cancerous tissues, but it was similar across the various stages of urothelial carcinoma (T(a)-T(4)). E-cadherin immunoreactivity decreased in urothelial cancer. Association of EphA2 and Ephrin A-1 expression was found to be significant between T(a) stage and T(1)-T(2) (P < 0.04) and T(a) and T(3)-T(4) stages (P < 0.0001). Adenovirus delivery of Ephrin A-1 inhibited proliferation of TCCSUP cells. CONCLUSION: EphA2 may serve as a novel target for bladder cancer therapy.

Adenoviridae↗
PubMed2006

Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects.

More than 14,000 people die from invasive transitional cell carcinoma (TCC) of the urinary bladder yearly in the United States. Cyclooxygenase (COX)-inhibiting drugs are emerging as potential antitumor agents in TCC. The optimal in vitro or in vivo systems to investigate COX inhibitor antitumor effects have not been defined. The purpose of this study was to determine COX-1 and COX-2 expression and antitumor effects of COX inhibitors in human TCC cell lines (HT1376, RT4, and UMUC3 cells) and xenografts derived from those cell lines. COX-2 expression (Western blot, immunocytochemistry) was high in HT1376, modest in RT4, and absent in UMUC3 cells in vitro. Similarly, COX-2 expression was noted in RT4 but not UMUC3 xenografts. COX-2 expression in HT1376 xenografts was slightly lower than that observed in vitro. None of four COX inhibitors evaluated (celecoxib, piroxicam, valeryl salicylate, and NS398) reduced TCC growth in standard in vitro proliferation assays at concentrations that could be safely achieved in vivo (< or =5 micromol/L). Higher celecoxib concentrations (> or =50 micromol/L) inhibited proliferation and induced apoptosis in all three cell lines. Celecoxib or piroxicam treatment in athymic mice significantly delayed progression of HT1376 xenografts, which express COX-2, but not UMUC3 xenografts that lack COX-2 expression. In conclusion, standard in vitro assays were not useful in predicting COX inhibitor antitumor effects observed in vivo. Athymic mice bearing TCC xenografts provide a useful in vivo system for COX inhibitor studies. Results of this study provide justification for further evaluation of COX inhibitors as antitumor agents against TCC.

Animals↗
PubMed2005

Expression and purification of the intact cytoplasmic domain of the human ephrin receptor A2 tyrosine kinase in Escherichia coli.

The ephrin receptor A2 (EphA2) is an integral membrane protein tyrosine kinase and a member of the Eph family, the largest known family of receptor tyrosine kinases. EphA2 overexpression is sufficient to transform normal epithelial cells into an aggressive, metastatic phenotype. In normal cells, EphA2 negatively regulates cell growth and invasiveness. Here we report expression of the intact cytoplasmic domain (juxtamembrane linker, tyrosine kinase, and sterile alpha motif domains) of the human EphA2 receptor in an Escherichia coli system. The expressed protein was purified to near homogeneity by use of metal chelation chromatography combined with removal of vector-encoded tags by specific proteolysis. The cytoplasmic domains of EphA2 are expressed as an active kinase, with the expressed protein found to contain phosphorylated tyrosine residues. In addition, protein tyrosine phosphorylation appears only after EphA2 expression is induced and is removable with alkaline phosphatase treatment. The enzyme was purified 5-fold in yields that average 10-30 mg/L of active EphA2 cytoplasmic domains, which will now be used for further biophysical and structural characterization.

Amino Acid Motifs↗
PubMed2005

Evaluation of the effect of dietary vegetable consumption on reducing risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers.

OBJECTIVE: To evaluate the effects of vegetable consumption and vitamin supplementation on the risk of developing transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. DESIGN: Case-control study. ANIMALS: 92 adult Scottish Terriers with TCC (cases) and 83 Scottish Terriers with other conditions (controls). PROCEDURE: Owners of dogs with TCC completed a questionnaire regarding their dogs' diet and intake of vitamin supplements in the year prior to diagnosis of TCC; owners of control dogs completed the questionnaire for a comparable time period. The risk (odds ratio [OR]) of developing TCC associated with diet and vitamin supplementation was determined by use of logistic regression. RESULTS: After adjustment for age, weight, neuter status, and coat color, there was an inverse association between consumption of vegetables at least 3 times/wk (OR, 0.30; 95% confidence interval [CI], 0.15 to 0.62) and risk of developing TCC. For individual vegetable types, the risk of developing TCC was inversely associated with consumption of green leafy vegetables (OR, 0.12; 95% CI, 0.01 to 0.97) and yellow-orange vegetables (OR, 0.31; 95% CI, 0.14 to 0.70). Consumption of cruciferous vegetables was not significantly associated with a similar reduction in risk of developing TCC (OR, 0.22; CI, 0.04 to 1.11). The power of the study to detect a 50% reduction in TCC risk associated with daily vitamin supplementation was considered low (25%). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that consumption of certain vegetables may prevent or slow the development of TCC in Scottish Terriers.

Animal Feed↗
PubMed2004

Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers.

OBJECTIVE: To determine whether use of topical flea and tick products increases the risk of transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. DESIGN: Case-control study. ANIMALS: 87 adult Scottish Terriers with TCC (cases) and 83 adult Scottish Terriers with other health-related conditions (controls). PROCEDURE: Owners of study dogs were recruited through private veterinary practices and the Scottish Terrier Club of America. History of exposure to flea and tick products 1 year prior to diagnosis of TCC for case dogs and during a comparable period for control dogs was obtained through a questionnaire. Risk of TCC associated with exposure to flea and tick products was determined by means of univariate and multiple logistic regression analysis. RESULTS: After adjustment for host factors, Scottish Terriers treated with topical spot-on flea and tick products containing fipronil or imidacloprid did not have an increased risk of TCC, compared with Scottish Terriers that had never been exposed to any flea and tick products. The risk of TCC associated with use of older topical flea and tick products such as shampoos, dips, powders, sprays, and collars could not be evaluated because of the low number of owners in the study population that had used such products. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that use of topical spot-on flea and tick products does not increase the risk of TCC in Scottish Terriers.

Administration, Topical↗
PubMed2004

Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers.

OBJECTIVE: To determine whether exposure to lawn or garden chemicals was associated with an increased risk of transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. DESIGN: Case-control study. ANIMALS: 83 Scottish Terriers with TCC (cases) and 83 Scottish Terriers with other health-related conditions (controls). PROCEDURE: Owners of study dogs completed a written questionnaire pertaining to exposure to lawn or garden chemicals during the year prior to diagnosis of TCC for case dogs and during a comparable period for control dogs. RESULTS: The risk of TCC was significantly increased among dogs exposed to lawns or gardens treated with both herbicides and insecticides (odds ratio [OR], 7.19) or with herbicides alone (OR, 3.62), but not among dogs exposed to lawns or gardens treated with insecticides alone (OR, 1.62), compared with dogs exposed to untreated lawns. Exposure to lawns or gardens treated with phenoxy herbicides (OR, 4.42) was associated with an increased risk of TCC, compared with exposure to untreated lawns or gardens, but exposure to lawns or gardens treated with nonphenoxy herbicides (OR, 3.49) was not significantly associated with risk of TCC. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that exposure to lawns or gardens treated with herbicides was associated with an increased risk of TCC in Scottish Terriers. Until additional studies are performed to prove or disprove a cause-and-effect relationship, owners of Scottish Terriers should minimize their dogs' access to lawns or gardens treated with phenoxy herbicides.

Animals↗
PubMed2004

Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of cisplatin administered with piroxicam, the antitumor activity and toxicity of cisplatin combined with piroxicam in dogs with oral malignant melanoma (OMM) and oral squamous cell carcinoma (SCC), and the effects of piroxicam on the pharmacokinetics of cisplatin in dogs with tumors. DESIGN: Prospective nonrandomized clinical trial. ANIMALS: 25 dogs. PROCEDURE: Dogs were treated with a combination of cisplatin (escalating dose with 6 hours of diuresis with saline [0.9% NaCI] solution) and piroxicam (0.3 mg/kg 10.14 mg/lb], PO, q 24 h). The initial cisplatin dose (50 mg/m2) was increased by 5 mg/m2 until the MTD was reached. Tumor stage and size were determined at 6-week intervals during treatment. The pharmacokinetics of cisplatin were determined in dogs receiving a combination of cisplatin and piroxicam during the clinical trial and dogs that were treated with cisplatin alone. RESULTS: 11 dogs with OMM and 9 dogs with SCC were included in the clinical trial. The MTD of cisplatin when administered in combination with piroxicam was 50 mg/m2. Tumor remission occurred in 5 of 9 dogs with SCC and 2 of 11 dogs with OMM. The most common abnormality observed was renal toxicosis. Clearance of cisplatin in dogs that were treated with cisplatin alone was not significantly different from that in dogs treated with a combination of cisplatin and piroxicam. CONCLUSIONS AND CLINICAL RELEVANCE: Cisplatin administered in combination with piroxicam had antitumor activity against OMM and SCC. The level of toxicity was acceptable, although renal function must be monitored carefully.

Animals↗
PubMed2004

Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1.

The EphA2 receptor tyrosine kinase is frequently overexpressed in invasive breast cancer cells. Moreover, these malignant cells have unstable cell-cell contacts, which preclude EphA2 from interacting with its ligand, EphrinA1, which is anchored to the membrane of adjacent cells. This defect is important because ligand binding causes EphA2 to transmit signals that negatively regulate tumor cell growth and survival, whereas the absence of ligand binding favors these same behaviors. In our present study, human adenoviral type 5 (HAd) vectors were engineered to express secreted-forms of EphrinA1. These vectors were used to infect MDA-MB-231 human breast cancer cells, or MCF-10A human breast epithelial cells providing matched controls. Infection with HAd-EphrinA1-Fc (HAd vector expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) caused increased EphA2 activation and turnover and consequently decreased tumor cell viability in soft agar assays. Consistent with this observation, infection of MDA-MB-231 cells with HAd-EphrinA1-Fc prevented tumor formation in xenograft models. Furthermore, therapeutic modeling via intratumoral inoculation revealed that HAd-EphrinA1-Fc significantly inhibited subsequent tumor growth as compared to matched controls. These results suggest that targeting of EphA2 with adenoviral vectors may have therapeutic value.

Adenoviridae↗
PubMed2003

Effects of the cyclooxygenase inhibitor, piroxicam, in combination with chemotherapy on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer.

The objectives of this study were: (a) to determine the antitumor activity and toxicity of a cyclooxygenase inhibitor (piroxicam) combined with cisplatin chemotherapy in dogs with naturally-occurring, invasive transitional cell carcinoma (TCC) of the urinary bladder; and (b) to determine the effects of this treatment on prostaglandin E(2) concentration, tumor cell proliferation and apoptosis, and angiogenesis. Pet dogs with naturally-occurring invasive TCC underwent complete tumor staging before and after 10 weeks of piroxicam/cisplatin treatment. Prostaglandin E(2) concentrations were determined by immunoassay in snap-frozen tumor tissues. Apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), proliferation (proliferating cell nuclear antigen), and microvessel density were determined in formalin-fixed tissues. Urine basic fibroblast growth factor and vascular endothelial cell growth factor concentrations were determined by immunoassay. Partial remission (> or =50% reduction in tumor volume) was noted in 6 of 12 dogs treated with piroxicam/cisplatin. Renal toxicity was dose-limiting. Apoptotic index doubled with treatment in 11 of 12 dogs but was not associated with tumor response. Proliferative index decreased in five dogs, and tumor decreased in size in three of the five dogs. Change in urine basic fibroblast growth factor and vascular endothelial cell growth factor was associated with tumor response. microvessel density was not associated with tumor response. In conclusion, piroxicam/cisplatin had antitumor activity against canine TCC, a disease that closely mimics human invasive urinary bladder cancer. Strategies to prevent renal toxicity of this protocol are needed. Induction of tumor apoptosis and reduction in angiogenic factor concentrations were observed, but additional studies are needed to further define the mechanisms of the antitumor activity of piroxicam/cisplatin.

Animals↗
PubMed2002

Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs.

OBJECTIVE: To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. DESIGN: Nonrandomized clinical trial. ANIMALS: 75 dogs with multicentric lymphoma. PROCEDURE: 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.

Animals↗
PubMed2002

Effects of the cyclooxygenase inhibitor, piroxicam, on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer.

The mechanisms by which cyclooxygenase inhibitors exert antitumor effects are not completely defined but are postulated to involve antiangiogenic effects and induction of apoptosis. In this study, we determined the effects of the cox inhibitor, piroxicam, on tumor response, apoptotic index, proliferative index, cyclooxygenase-2 expression, prostaglandin E(2) concentration, tumor microvessel density, and urine basic fibroblast growth factor and vascular endothelial growth factor concentrations in pet dogs with naturally occurring invasive transitional cell carcinoma of the urinary bladder. Piroxicam caused reduction in tumor volume in 12 of 18 dogs, and this was strongly associated with induction of apoptosis (Fisher's exact test P < 0.015) and reduction in urine basic fibroblast growth factor concentration.

Animals↗
PubMedDate not supplied

Canine anal sac adenocarcinomas: clinical presentation and response to therapy.

A retrospective study of 43 dogs with anal sac adenocarcinoma (ASAC) was performed to characterize the clinical presentation and response to treatment. Clinical signs at presentation varied considerably, with signs related either to sublumbar nodal metastasis (tenesmus or constipation) or hypercalcemia (polyuria-polydipsia and anorexia) being the most frequent findings. At the time of presentation, 23 (53%) dogs had hypercalcemia and 34 (79%) had metastases, with the regional lymph nodes (31 dogs, 72%) being the most common site of metastasis. A variety of chemotherapeutic agents were administered, with partial remission (PR) recorded in 4 of 13 (31%) dogs treated with cisplatin and in 1 of 3 (33%) dogs treated with carboplatin. The median survival for all dogs was 6 months (range, 2 days-41 months). There was no statistical association between the presence of hypercalcemia and survival, although the power of the study to detect an increase in survival of 3 months was low (.33). We conclude that platinum chemotherapy has antitumor activity in canine apocrine gland carcinoma and that further study of these agents is warranted.

Adenocarcinoma↗
PubMedDate not supplied

Influence of host factors on survival in dogs with malignant mammary gland tumors.

The purpose of our study was to determine if specific host factors, such as age at diagnosis, obesity, and hormone status, influence the prognosis of canine mammary gland carcinomas and to confirm if previously reported risk factors (ie, histologic subtype, tumor size, and World Health Organization [WHO] stage) were important in a large series of affected dogs. Ninety-nine female dogs with mammary gland carcinomas, no previous therapy, an excisional biopsy, and known cause of death were studied. No significant association with survival was noted for age at diagnosis (chronologic or physiologic), obesity, or hormone status (ie, spayed versus intact, regardless of time of being spayed). Of the tumor factors analyzed, the histologic subtype anaplastic carcinoma (P = .02), WHO stage I (P = .01), evidence of metastasis at the time of diagnosis (P = .004), and tumor size of 3 cm or smaller (P = .005) all significantly influenced survival. Dogs that were classified as having tumor-related mortality had a shorter postoperative survival compared to dogs that died of other causes (14 months versus 23 months; P = .03). In conclusion, histologic subtype, WHO stage, and tumor size remain important prognostic factors in canine mammary gland tumors. Further study of other prognostic factors is needed to determine which tumors are adequately addressed with local therapy only and which dogs may require adjuvant treatment with chemotherapy.

Aging↗
PubMedDate not supplied

Canine transitional cell carcinoma.

Transitional cell carcinoma (TCC) of the urinary bladder, the most common malignancy of the urinary tract in dogs, is challenging to both diagnose and treat effectively. The prevalence of this disease may be increasing. The etiology of canine TCC is likely multifactorial. Epidemiological studies of TCC in the dog have revealed a number of risk factors, including breed and female gender, as well as environmental factors, such as insecticide exposure. This tumor is difficult to remove surgically and responds poorly to chemotherapy. The efficacy of radiotherapy and other treatment modalities needs further investigation. Cyclooxygenase-inhibiting drugs have some activity against TCC, and studies to further define these effects are ongoing. Use of the tumor/node/ metastasis (TNM) classification scheme for bladder cancer has allowed for the identification of prognostic factors. Urinary tract obstruction and metastatic disease remain challenges to treat. Work with canine TCC has demonstrated how closely this disease resembles human invasive urinary bladder cancer. Therefore, future research has the potential to benefit both dogs and humans with TCC.

Animals↗
PubMedDate not supplied

Prognosis following surgical excision of canine cutaneous mast cell tumors with histopathologically tumor-free versus nontumor-free margins: a retrospective study of 31 cases.

The purpose of this study was to determine if the presence of histopathologically tumor-free versus nontumor-free margins was prognostic for relapse or tumor-related death in dogs following surgical excision of single or multiple cutaneous mast cell tumors confined to the skin without evidence of metastasis to lymph nodes or other noncutaneous sites. Differences in tumor-related death or frequency of relapse between the two groups were not significant. Failure to achieve histopathological tumor-free margins frequently did not lead to local relapse. All tumor-related deaths occurred following local relapse. The lack of statistical support for an association between prognosis and histopathological tumor-free versus nontumor-free margins may be a result of small sample size.

Animals↗
PubMedDate not supplied

Influence of asparaginase on a combination chemotherapy protocol for canine multicentric lymphoma.

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.

Animals↗