Pharmacokinetic and Phase I Evaluation of Carboplatin in Dogs

Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD₅₀) or a 5% incidence of severe toxicity (SEV₅). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD₅₀ and SEV₅ for the first treatment course were 340 and 278 mg/M², respectively. MOD₅₀ and SEV₅ values for the first plus second treatment courses were 327 and 231 mg/M², respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541/μL and 62,600/μL, respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T_1/2), area-under-the-curve and total body clearance (CL_b) were not dose dependent. Volume of distribution (VD_ss) significantly increased with dose only between 100 and 150 mg/M², not between 150 and 300 mg/M². Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity. (Journal of Veterinary Internal Medicine 1993; 7:235–240. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Electrophoretic evaluation of sera from dogs with cancer.

A quantitative electrophoretic method was developed for evaluating sera from dogs with naturally occurring malignant tumors. Electrophoretic migration ratios (EMR) were devised to standardize characteristic protein components and to analyze alterations in mobility of these protein components, using a computerized densitometric technique. Sera values from dogs with lymphosarcomas, osteosarcomas, and mammary tumors were compared, using conventional methods of statistical analysis. Results indicate a statistical difference existed between mean values of EMR and alpha2-globulins of sera from dogs with tumors and those values from normal dogs. In addition, unique EMR and concentration of protein components were identified for dogs with lymphosarcomas, osteosarcomas, and mammary tumors.     

Radiotherapy of soft tissue sarcomas in dogs

Megavoltage radiotherapy was administered to 42 dogs with soft tissue sarcoma. Acceptable local control of these aggressive tumors was achieved after one year of treatment. Control rates of 48 and 67% were obtained at doses of 45 and 50 gray (Gy), respectively. At 2 years, control rates decreased to 33% at the dose of 50 Gy. Serious complications developed in 4 of 42 dogs at doses of 40 to 50 Gy. The estimated dose with a 50% probability for causing serious complications was 54 Gy, given in 10 fractions. We believe that the large doses per fraction used in this study probably led to an increased probability for necrosis. Hemangiopericytomas seemed to be more responsive than fibrosarcomas. Only 2 of 11 recurrent tumors were controlled with surgery. Good local control was achieved with radiation alone for one year at doses with a low probability for serious complications; however, higher total radiation doses or combined modalities, such as surgery and radiation or radiation and hyperthermia, may be needed for longer-term control.     

The role of hypoxia in canine cancer

Human oncology has clearly demonstrated the existence of hypoxic tumours and the problematic nature of those tumours. Hypoxia is a significant problem in the treatment of all types of solid tumours and a common reason for treatment failure. Hypoxia is a negative prognostic indicator of survival and is correlated with the development of metastatic disease. Resistance to radiation therapy and chemotherapy can be because of hypoxia. There are two dominant types of hypoxia recognized in tumours, static and intermittent. Both types of hypoxia are important in terms of resistance. A variety of physiological factors cause hypoxia, and in turn, hypoxia can induce genetic and physiological changes. A limited number of studies have documented that hypoxia exists in spontaneous canine tumours. The knowledge from the human literature of problematic nature of hypoxic tumours combined with the rapid growth of veterinary oncology has necessitated a better understanding of hypoxia in canine tumours.     

Activation of defence in sweet pepper, Capsicum annum, by cis-jasmone, and its impact on aphid and aphid parasitoid behaviour

BACKGROUND: Two important pests of the sweet pepper, Capsicum annuum, are the peach potato aphid, Myzus persicae, and the glasshouse potato aphid, Aulacorthum solani. Current aphid control measures include the use of biological control agents, i.e. parasitic wasps, but with varying levels of success. One option to increase parasitoid efficiency is to activate plant defence. Therefore, sweet pepper plants were treated with the naturally occurring plant defence activator cis-jasmone, and its impact upon the behaviour and development of aphids and aphid parasitoids was investigated. RESULTS: Growth rate studies revealed that the intrinsic rate of population increase of A. solani and M. persicae on sweet pepper plants treated with cis-jasmone (cJSP) was not affected compared with untreated plants (UnSP), but the positive behavioural response of alate M. persicae towards the volatile organic compounds (VOCs) from UnSP was eliminated by cis-jasmone treatment 48 h previously (cJSP48). In addition, the aphid parasitoid Aphidius ervi preferred VOCs from cJSP48 compared with UnSP, and a significant increase in foraging time was also observed on cJSP. Analysis of VOCs collected from cJSP48 revealed differences compared with UnSP. CONCLUSION: There is evidence that treatment with cis-jasmone has the potential to improve protection of sweet pepper against insect pests. © Crown copyright 2012. Reproduced with permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.     

Whole-Body Hyperthermia

Whole-body hyperthermia is the controlled elevation of systemic temperature for therapeutic purposes. Historically, this treatment has been used for symptomatic control of many diseases. Recently, the potential therapeutic benefit of whole-body hyperthermia in the management of neoplastic disease has been investigated vigorously. The rationale for improved tumor control is based on heat-induced enhancement of the antineoplastic effects of radiation and chemotherapy. Although the complex biologic interaction of heat and radiation has been studied for many years, chemotherapy combined with hyperthermia has been studied less thoroughly. Despite a lack of adequate long-term laboratory and clinical investigation, use of whole-body hyperthermia with chemotherapy and radiotherapy is a logical and potentially powerful therapeutic strategy for neoplasia. Relevant issues regarding the application of whole-body hyperthermia with more traditional modes of therapy are being studied in preliminary clinical trials involving dogs and humans. Identification of optimal timing and sequencing of adjunctive therapy, proper cytotoxic drug application, methods to further minimize toxicity, and heat-sensitive tumor types will lead to expanded clinical use of whole-body hyperthermia. The historical development, clinical rationale, and application of whole-body hyperthermia for the control of disseminated or refractory neoplasia in humans and dogs is reviewed.     

An epizootic of bovine cysticercosis.

In March, 1973, a large feedlot near Phoenix, AZ, reported an increased incidence of bovine cysticercosis. Approximately 10% of cattle sent to slaughter from January to April, 1973, were infected with the cysticercus stage of Taenia saginata. One employee who worked at the feed mill and loaded hay in the fields was also found to be infected with T saginata. Recommendations for control of similar epizootics included educating employees about mode of transmission and improved personal hygiene, the inauguration of a surveillance program that included examination of employees prior to employment and periodically thereafter, maintenance of animal source and destination records, restriction of unauthorized personnel to critical areas, and periodic microbiologic assay of water supply.     

A REVIEW OF TREATMENT PLANNING AND DOSE CALCULATION IN VETERINARY RADIATION ONCOLOGY

Because radiation cell killing follows Poisson statistics, radiation dose response curves for tumors and normal tissue response are sigmoidal in shape. This shape implies that small errors in delivery of radiation dose can result in large changes in the probability of normal tissue necrosis or tumor control. Thus it is important for veterinarians involved with radiation oncology to be familiar with the basic aspects of radiation physics and dose calculation as they relate to radiation therapy. In this paper, we present a review of pertinent physics and treatment planning relative to orthovoltage and cobalt irradiation. The usefulness of radiation treatment planning computers is emphasized for improving the radiation oncologist's knowledge of dose distribution and selection of the optimum treatment plan.     

Use of radiation and/or hyperthermia for treatment of mast cell tumors and lymphosarcoma in dogs

Radiation alone can be used to treat mast cell tumors that are not likely to metastasize (that is, differentiated or localized lymphorecticular tumors). In patients with mast cell tumors that are likely to metastasize (that is, undifferentiated, metastatic mast cell disease or generalized lymphoreticular neoplasms), radiation should not be used as the only treatment agent. In these patients, treatment combinations of hyperthermia/chemotherapy and radiation/hyperthermia/chemotherapy have been shown to have promise, but these treatment combinations need to be evaluated in prospective trials.     

Phase I Evaluation of Doxorubicin and Whole-body Hyperthermia in Dogs with Lymphoma

Fifteen previously untreated dogs with histologically confirmed, high-grade multicentric lymphoma were entered into a phase I study to evaluate combined doxorubicin and whole-body hyperthermia (DOX/WBH). Groups of three, four, and eight dogs were treated with whole-body hyperthermia and concurrent doxorubicin at 12 mg/m2, 24 mg/m2 and 30 mg/m2, respectively, after one doxorubicin induction dose at 30 mg/m2. Plateau temperature (42 +/- 0.1 degree C) was maintained for 90 minutes using a radiant heating device. A total of five DOX/WBH treatments per dog were planned, and these were given every 21 days. Treatment-related toxicity was not seen in the 12-mg/m2 doxorubicin dose group. Tumor progression prohibited administration of more than three DOX/WBH treatments to any dog in the 12-mg/m2 group. Premature ventricular contractions developed after the fifth treatment in one of the four dogs treated with 24 mg/m2 of doxorubicin. Two dogs (25%) in the 30-mg/m2 dose group had treatment-related toxicity. One dog experienced acute serious myelosuppression 1 week after the third treatment. This dog received all planned DOX/WBH treatments. Asymptomatic cardiac toxicosis consisting of decreased ejection fraction and fractional shortening developed in the second dog. This dog received only two DOX/WBH treatments. The three dogs treated at 12 mg/m2 had partial responses of short duration (60-83 days). Four dogs treated at 24 mg/m2 had complete responses for 150, 164, 186, and 200 days. Eight dogs treated at 30 mg/m2 had complete responses with a mean and median duration of 241 and 190 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)