Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibility of their exploitation as surrogate biomarkers for pharmacodynamic drug activity/exposure and patient benefit. A postulated mechanism for these changes is that they are tumor-dependent, resulting from drug-induced decreases in vascular function, increases in tumor hypoxia, and changes in hypoxia-regulated genes. However, here we report that an identical pattern of change is observed in normal nontumor-bearing mice treated with SU11248/sunitinib, a small-molecule inhibitor of VEGF and PDGF RTKs. The changes were dose-dependent, plateaued after 4 days of consecutive treatment, reversed after discontinuation of therapy, and correlated with antitumor activity. Altered protein expression was found in a broad variety of tissues, and dose-dependent elevations were observed of several plasma proteins previously unassociated with this class of inhibitor, including G-CSF, SDF-1␣, SCF, and osteopontin. Our results suggest that observed sunitinib-induced molecular plasma changes, including those both directly and indirectly targeted by drug, represent a systemic tumor-independent response to therapy and may correlate with the most efficacious antitumor doses, potentially having utility for defining the optimal biologic dose range for this drug class but not as predictive markers of tumor response or clinical benefit. They may also be relevant to drug-associated toxicities, drug resistance, and observed rapid tumor (re)growth seen after cessation of therapy.angiogenesis ͉ optimal biological dosing ͉ SU11248 ͉ surrogate biomarkers

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. Cyclooxygenaseinhibiting 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.Key words: Animal models; Bladder cancer; Chemotherapy; Cyclooxygenase; Piroxicam; Risk factors.U rinary bladder cancer in dogs is a challenging disease to diagnose, stage, and treat. Fortunately, urinary bladder cancer is uncommon in the dog, comprising Ͻ2% of all reported canine malignancies. 1 Transitional cell carcinoma (TCC) is the most common neoplasm affecting the urinary bladder of dogs. In this article, we review current knowledge of canine TCC with regard to frequency, etiology, histopathological characteristics, cellular and molecular features, response to therapy, and prognostic factors. We also discuss why canine TCC is a good model of human invasive bladder cancer. FrequencyAlthough the true prevalence of canine TCC is not known, it is the most common form of urinary tract cancer in the dog and comprises 1.5-2% of all canine cancers. 2,3 The hospital prevalence, or proportionate morbidity, of bladder cancer at university-based veterinary hospitals appears to be increasing. 4 A search of the Veterinary Medical Data Base (VMDB) 5 from 1975 to 1995 showed a continuous increase in the prevalence of bladder cancer, with prevalence defined as the number of dogs with bladder cancer divided by the total number of individual dogs seen for any reason at the same participating university veterinary hospitals. 4 Etiology and Risk FactorsThe etiology of canine TCC is most likely multifactorial. Risk factors that have been identified include exposure to topical insecticides for flea and tick control, exposure to marshes that have been sprayed for mosquito control, obe- University, West Lafayette, IN. Reprint requests: Deborah W. Knapp, DVM, MS, DACVIM, Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907-1248; e-mail: knappdw@purdue.edu. Submitted December 28, 2001; Revised April 23, 2002; Accepted June 17, 2002. Copyright ᭧ 2003 sity, ...

No abstract

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% NaCl] solution) and piroxicam (0.3 mg/kg [0.14 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. ( J Am Vet Med Assoc 2004;224:388–394)

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. U rinary bladder cancer in dogs is a challenging disease to diagnose, stage, and treat. Fortunately, urinary bladder cancer is uncommon in the dog, comprising 2% of all reported canine malignancies. 1 Transitional cell car-cinoma (TCC) is the most common neoplasm affecting the urinary bladder of dogs. In this article, we review current knowledge of canine TCC with regard to frequency, etiol-ogy, histopathological characteristics, cellular and molecular features, response to therapy, and prognostic factors. We also discuss why canine TCC is a good model of human invasive bladder cancer. Frequency Although the true prevalence of canine TCC is not known, it is the most common form of urinary tract cancer in the dog and comprises 1.5-2% of all canine cancers. 2,3 The hospital prevalence, or proportionate morbidity, of bladder cancer at university-based veterinary hospitals appears to be increasing. 4 A search of the Veterinary Medical Data Base (VMDB) 5 from 1975 to 1995 showed a continuous increase in the prevalence of bladder cancer, with prevalence defined as the number of dogs with bladder cancer divided by the total number of individual dogs seen for any reason at the same participating university veterinary hospitals. 4 Etiology and Risk Factors The etiology of canine TCC is most likely multifactorial. Risk factors that have been identified include exposure to topical insecticides for flea and tick control, exposure to marshes that have been sprayed for mosquito control, obe-Medicine 0891-6640/03/1702-0002/$3.00/0 sity, possibly cyclophosphamide a administration, female sex, and specific breeds (eg, Scottish Terrier). 4,6-8 In addition to these risk factors, a 1981 study showed a significant positive correlation between the proportional morbidity ratios for canine bladder cancer and the overall level of industrial activity in the host county of the veterinary hospital. 9 ...

Vascular endothelial growth factor

Invasive transitional cell carcinoma (TCC) of the urinary bladder responds poorly to medical therapy. Combining platinum chemotherapy with a cyclooxygenase (cox) inhibitor has shown promise against canine TCC, where the disease closely mimics the human condition. A phase II clinical trial of carboplatin combined with the cox inhibitor, piroxicam, was performed in 31 dogs with naturally occurring, histopathologically confirmed, measurable TCC. Complete tumour staging was performed before and at 6-week intervals during therapy. Tumour responses in 29 dogs included 11 partial remissions, 13 stable disease and five progressive disease. Two of the 31 dogs were withdrawn prior to the re-staging of the tumour. Gastrointestinal toxicity was observed in 23 dogs. Hematologic toxicity was noted in 11 dogs. The median survival was 161 days from first carboplatin treatment to death. In conclusion, carboplatin/piroxicam induced remission in 40% of dogs providing evidence that a cox inhibitor enhances the antitumour activity of carboplatin. The frequent toxicity and limited survival, however, do not support the use of this specific protocol against TCC.

Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer.