Background: Vincristine (VCR) is a mono-chemotherapy for canine transmissible venereal tumor (CTVT). L-asparaginase (LAP) is usually used in combination with other drugs. Previously, LAP-VCR protocol was applied for the CTVT-VCR-resistant cases. However, there were a few reports about using this protocol since the first visit.Aims: To firstly investigate the effectiveness of combining chemotherapy (Vincristine and L-asparaginase, VCR-LAP) in normal CTVT case. Secondly, to compare this protocol with the conventional (Vincristine, VCR) protocol before and during treatment in 24 CTVT dogs.Materials and Methods: Clinical signs, tumor relative volume, and histopathological change [amount of CTVT cells, tumor-infiltrating lymphocytes (TILs), TILs/CTVT ratio, collagen area, and Ki-67 proliferative index (PI)] were the treatment evaluation parameters. Moreover, transcriptome analysis of apoptotic (Bcl-2, Bax), drug-resistant genes (ABCB1, ABCG2), and BCL-2 and BAX expression were also included.Results: Both protocols gave the decreased tumor volume, increased TILs/CTVT ratios and collagen area in the mass. Interestingly, the combination protocol decreased treatment time. There were two resistant cases after treatment with VCR. The expression of Bcl-2 and Bax were decreased, and this may indicate the better response after treatment. Moreover, both drug resistant genes did not increase after treatment.Conclusion: The main finding of this study is that the combination protocol did not only decrease treatment duration time but also gave the effectiveness of treatment outcomes in CTVT cases. Therefore, the application of the new protocol could be used by the field practitioners.
Saliva biomarkers are suitable for monitoring the therapeutic response of canine oral melanoma (COM), because saliva directly contacts the tumor, and saliva collection is non-invasive, convenient and cost effective. The present study aimed to investigate novel biomarkers from the salivary proteome of COM treated with surgery and a chemotherapy drug, carboplatin, 1–6 times, using a liquid chromatography–tandem mass spectrometry approach. The expression of a potential salivary biomarker, ubiquitin D (UBD), was observed and verified by western blot analysis. A significantly increased ratio of free UBD (fUBD) to conjugated UBD (cUBD) was shown in the pre-surgery stage (PreS) in OM dogs with short-term survival (STS) (less than 12 months after surgery) compared with that with long-term survival (more than 12 months after surgery). In dogs with STS, the ratio was also shown to be augmented in PreS compared with that after surgery, followed by treatment with carboplatin twice, 4 and 5 times [After treatment (AT)2, AT4 and AT5]. In addition, the expression of fUBD was enhanced in PreS compared with that of AT2 in the STS group. In conclusion, this study revealed that a ratio of fUBD to cUBD in PreS was plausibly shown to be a potential prognostic biomarker for survival in dogs with OM.
Heteroduplex polymerase chain reaction for antigen receptor rearrangements (hPARR) was developed to monitor minimal residual disease (MRD) in canine B- and T-cell lymphomas treated with the modified L-COP or L-CHOP protocol. Thirty-five dogs were recruited in this study and their neoplastic lineages were determined by immunophenotyping with Pax5 and CD3. Peripheral blood leukocytes were collected prior to and during chemotherapy in weeks 4, 9 and 13 to detect MRD by hPARR. Twenty-eight dogs (80%) had B-cell lymphoma while seven dogs (20%) had T-cell lymphoma. A monoclonal band was detected in 11 cases that showed complete or partial remission before tumour relapse and no response to the current treatment without statistical difference in clinical outcomes; however, the treatment response had an association with the MRD result (P < 0.05). Modified L-CHOP prolonged median progression-free survival as compared to modified L-COP (215 days vs. 93 days; P < 0.05). Substage b had shorter progression-free survival than substage a (90 days vs. 215 days; P < 0.05). Clinical stage III affected median overall survival time when compared to clinical stages IV and V (432, 173 and 118 days, respectively; P < 0.05). hPARR could be used for screening refractory lymphoma together with lymph node measurement in routine clinical cases.
The main problems that cause unresponsiveness to an anti-neoplastic drug are the overexpression of drug resistant and anti-apoptotic proteins in tumor cells. In a rescue protocol we evaluated the ability of toceranib phosphate concurrent with lomustine (CCNU) or L-asparaginase and vincristine to decrease drug resistant and apoptotic proteins in relapsed and refractory canine lymphomas. The peripheral blood samples were collected before and after the rescue treatment from fourteen dogs that were refractory to cyclophosphamide-vincristine-prednisolone (COP) or COP-doxorubicin (CHOP) treatment and had recurrent multicentric lymphoma. The mRNA expression level of ABCB1, ABCG2, Bcl2 and Bax were determined by quantitative real-time PCR. The fold-change in ABCB1, ABCG2, Bcl2 and Bax mRNA levels were analyzed in correlation with the progression-free survival (PFS). After the rescue treatment, the ABCB1 and ABCG2 mRNA expression levels were 1.57- and 1.85-fold lower (p = 0.4 and p = 0.87), respectively, compared to pre-treatment. Bcl2/Bax ratio was numerically but not significantly decreased 1.02-fold (p = 0.74). The overall response rate of this protocol was 50% with a median PFS of 79 days (range 14-207 days). The low medians of relative expression levels of ABCB1, ABCG2 and Bcl2/Bax ratio group did not correlate with the clinical outcomes when compared to the high medians of relative expression levels, and likewise with the clinical stage, immunophenotype, histological grade and sub-stage. Therefore, the administration of a rescue drug with toceranib phosphate might be beneficial in refractory and relapsed canine lymphoma.
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