Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development.

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Rationally designed nanovehicles to overcome cancer chemoresistance.

Each year more than 65,000 people are diagnosed with urinary bladder cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to improve the management of bladder cancer. Naturally occurring bladder cancer in dogs very closely mimics human invasive bladder cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder cancer complements experimentally induced rodent tumors in regard to animal models of bladder cancer. Results of cellular and molecular studies and -omics analyses in dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as dogs. Clinical treatment trials in pet dogs with TCC are considered a win-win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using dogs with naturally occurring TCC.

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Urinary Bladder Cancer in Dogs, a Naturally Occurring Model for Cancer Biology and Drug Development

Nanocarrier-based systems for targeted and site specific therapeutic delivery.

Clinical cancer research.

Background
Transitional cell carcinoma (TCC) of the urinary bladder of dogs can be a difficult cancer to treat, and effective therapies are limited. Vinblastine has been used in humans with TCC and has potent anti-proliferative effects against canine TCC cells in vitro.

Objectives
To determine the antitumor activity and toxicoses of vinblastine in dogs with urinary bladder TCC.

Animals
Animals selected were 28 privately owned dogs that presented to the Purdue University Veterinary Teaching Hospital (PUVTH) with measurable, histologically confirmed TCC.

Methods
Prospective clinical trial: The starting vinblastine dosage was 3.0 mg/m2IV every 2 weeks. Treatment continued until cancer progression or unacceptable toxicoses occurred. Complete evaluations (physical exam, complete blood count [CBC], serum biochemical profile, urinalysis, thoracic radiography, abdominal ultrasound [US]) were performed at 8-week intervals. Urinary tract US with bladder tumor mapping was performed monthly. Toxicoses were graded according to Veterinary Co-Operative Oncology Group (VCOG) criteria.

Results
Tumor responses included 10 (36%) partial remission, 14 (50%) stable disease, and 4 (14%) progressive disease. The median progression free interval was 122 days (range, 28–399 days). The median survival time was 147 days (range, 28–476 days) from 1st vinblastine treatment to death and 299 days (range, 43–921 days) from diagnosis to death. The majority of dogs (27 of 28) did not have clinically relevant adverse effects. Seventeen of 28 (61%) dogs required dosage reductions because of neutropenia.

Conclusion and Clinical Importance
Vinblastine has antitumor activity against TCC in dogs and can be considered another treatment option for this cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2011.00796.x

Clinical trial of vinblastine in dogs with transitional cell carcinoma of the urinary bladder.

Folate receptors (FR) may be of use for targeted delivery of cytotoxic drugs in invasive urothelial carcinoma (iUC), for which improved therapy is needed. FR expression and function in iUC were explored and the antitumor activity and toxicity of a folate-targeted vinblastine conjugate were evaluated in dogs with naturally occurring iUC, an excellent model for human iUC. FR immunohistochemistry was carried out on iUC and normal human and dog bladder tissues together with nuclear scintigraphy in dogs to monitor iUC folate uptake. Dose escalation of a folate-targeted vinblastine compound, EC0905, was conducted in dogs with biopsy-confirmed, FR-positive iUC. FRs were detected by immunohistochemistry (PU17) in most primary iUC and many nodal and lung metastases from dogs, and scintigraphy confirmed folate uptake in both primary and metastatic lesions. The maximum tolerated dose of EC0905 in dogs was 0.25 mg/kg IV weekly, with neutropenia at higher doses. Tumor responses included partial remission (≥50% reduction in tumor volume) in five dogs and stable disease (

https://cancerres.aacrjournals.org/content/canres/early/2013/01/10/0008-5472.CAN-12-2101.full.pdf

Targeting Folate Receptors to Treat Invasive Urinary Bladder Cancer

Background: Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs The most frequent cause of death is urinary obstruction from the primary tumor Standard medical therapy for TCC is only partially effective



Hypothesis/Objectives: Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption



Animals: Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder



Methods: A prospective phase I trial was performed MMC was given intravesically (600 μg/mL initial concentration) for 1 h/d for 2 consecutive days each month The MMC concentration was escalated to a maximum of 800 μg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC



Results: The MTD of MMC based on local toxicoses was 700 μg/mL (1-h dwell time, 2 consecutive days) In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC Five dogs had partial remission, and 7 dogs had stable disease



Conclusions: Intravesical MMC has antitumor activity in dogs with invasive TCC Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2010.0569.x

Phase I Clinical Trial and Pharmacokinetics of Intravesical Mitomycin C in Dogs with Localized Transitional Cell Carcinoma of the Urinary Bladder

Determining the dimensions of transitional cell carcinomas (TCCs) of the urinary bladder in dogs is important in assessing tumor progression and the response to treatment. The primary aim of this study was to evaluate the reliability of a standardized two-dimensional (2-D) ultrasound (US) protocol performed by a single experienced operator. Secondary aims were to compare World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, and to compare measurements by two operators following these guidelines. These were evaluated by inter-operator and intra-operator reliability using the concordance correlation coefficient (CCC) and Cohen's κ statistics, which demonstrated substantial to better agreement by an experienced operator using either set of guidelines. It was demonstrated that 2-D US provides a reliable means to determine the dimensions of urinary bladder TCC when an experienced operator used a standardized protocol. In a subset of dogs, urinary bladder distension was varied, which resulted in differences in measurement with 2-D US and computed tomography.

Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors.

The purpose of this study was to determine the effects of a nonselective cyclooxygenase (cox) inhibitor and of a selective cox-2 inhibitor on the renal toxicity of cisplatin. Cisplatin with or without a cox-1 inhibitor (SC560), a cox-2 inhibitor (SC236), or a nonselective cox inhibitor (piroxicam) was administered to Sprague–Dawley rats. Renal toxicity was assessed by serum creatinine concentration (SCR), urine specific gravity (USG), and histopathologic lesion score (HLS). Acutely, the SCR was significantly higher in rats receiving cisplatin/SC560 (1.62 ± 0.34 mg/dl) or cisplatin/piroxicam (2.0 ± 0.41 mg/dl) than in rats receiving cisplatin alone (1.09 ± 0.40 mg/dl). The apparent increase in SCR in the rats receiving cisplatin/SC236 (1.58 ± 0.31) was not significantly different from that of rats receiving cisplatin alone (1.09 ± 0.40 mg/dl). No significant differences in USG or HLSs were noted between rats receiving cisplatin alone and cisplatin combined with any cox inhibitor. In a chronic study, no differences in renal toxicity were found between rats treated with cisplatin alone and cisplatin/SC236 or cisplatin/piroxicam. The acute rise in SCR following cisplatin treatment can be worsened by the addition of cox inhibitors, especially those that inhibit cox-1.

Lindsey M. Fourez

Papers

Clinical trial of vinblastine in dogs with transitional cell carcinoma of the urinary bladder.

Targeting Folate Receptors to Treat Invasive Urinary Bladder Cancer

Phase I Clinical Trial and Pharmacokinetics of Intravesical Mitomycin C in Dogs with Localized Transitional Cell Carcinoma of the Urinary Bladder

Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors.

Effects of cyclooxygenase inhibitor treatment on the renal toxicity of cisplatin in rats.