Determination of MDR1 gene expression for prediction of chemotherapy tolerance and treatment outcome in dogs with lymphoma

Gramer, Irina; Kessler, Martin; Geyer, Joachim

doi:10.1111/vco.12051

Cited by 14 publications

(15 citation statements)

References 30 publications

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“…Although pre-treatment P-gp, MRP1 and BCRP mRNA expression were not predictive of treatment outcome in dogs with multicentric lymphoma [ 20 , 108 ], P-gp mRNA expression in the peripheral blood was found to correlate with the likelihood of chemotherapy-related toxicity [ 140 ].…”

Section: Drug Resistance Due To Abc-transporters In Canine Lymphommentioning

confidence: 99%

Mechanisms of Drug Resistance in Veterinary Oncology— A Review with an Emphasis on Canine Lymphoma

Zandvliet

Teske

2015

Veterinary Sciences

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Drug resistance (DR) is the major limiting factor in the successful treatment of systemic neoplasia with cytotoxic chemotherapy. DR can be either intrinsic or acquired, and although the development and clinical implications are different, the underlying mechanisms are likely to be similar. Most causes for DR are pharmacodynamic in nature, result from adaptations within the tumor cell and include reduced drug uptake, increased drug efflux, changes in drug metabolism or drug target, increased capacity to repair drug-induced DNA damage or increased resistance to apoptosis. The role of active drug efflux transporters, and those of the ABC-transporter family in particular, have been studied extensively in human oncology and to a lesser extent in veterinary medicine. Methods reported to assess ABC-transporter status include detection of the actual protein (Western blot, immunohistochemistry), mRNA or ABC-transporter function. The three major ABC-transporters associated with DR in human oncology are ABCB1 or P-gp, ABCC1 or MRP1, and ABCG2 or BCRP, and have been demonstrated in canine cell lines, healthy dogs and dogs with cancer. Although this supports a causative role for these ABC-transporters in DR cytotoxic agents in the dog, the relative contribution to the clinical phenotype of DR in canine cancer remains an area of debate and requires further prospective studies.

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Section: Drug Resistance Due To Abc-transporters In Canine Lymphommentioning

confidence: 99%

Mechanisms of Drug Resistance in Veterinary Oncology— A Review with an Emphasis on Canine Lymphoma

Zandvliet

Teske

2015

Veterinary Sciences

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“…ATP‐binding cassette superfamily (ABC) proteins such as P‐glycoprotein (P‐gp) or multidrug resistance‐associated proteins may be involved in the development of resistance to first‐line chemotherapy . ABC protein superfamily proteins should not mediate resistance to alkylating agents, so their use in a rescue setting is appealing…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a multi‐agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non‐Hodgkin high‐grade lymphomas

Tanis

Mason

Maddox

et al. 2018

Vet Comparative Oncology

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The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified-LOPP protocol that does not include vincristine (LPP) and is administered on a 21-day cycle. Medical records of dogs with high-grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty-one dogs were included. Twenty-five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non-responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity-profile and minimizes in-hospital procedures.

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“…Cases in which platelets showed clotting and the neutrophil number was above the normal range were also excluded. Side effects occurring after the first chemotherapy treatment, including neutropenia, thrombocytopenia, hypohemoglobin, diarrhea, and vomiting, were scored using the scoring system of the Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE) [921]. According to this scoring system, two treatment tolerance categories were defined: well-tolerated with a total score of 0 to 5 and adversely affected with a total score ≥ 6 [9].…”

Section: Methodsmentioning

confidence: 99%

Development of an oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and association between genotypes and chemotherapy side effects

Lee

Lin

et al. 2019

J Vet Sci

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Canine MDR1 gene mutations produce translated P-glycoprotein, an active drug efflux transporter, resulting in dysfunction or over-expression. The 4-base deletion at exon 4 of MDR1 at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G allele of the c.-6-180T>G variation in intron 1 of MDR1 (single nucleotide polymorphism [SNP] 180) causes P-glycoprotein over-expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations are reported to be common in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. Genotype distribution in Taiwan was also investigated. An oligonucleotide microarray was successfully developed for the detection of both genotypes and was applied to clinical samples. No 4-base deletion mutant allele was detected in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all dog breeds, not only in collies. The chemotherapy adverse effect percentages of the SNP 180 T/T, T/G, and G/G genotypes were 16.7%, 6.3%, and 0%, respectively. This study describes an efficient way for MDR1 gene mutation detection, clarifying genotype distribution, and the association with chemotherapy.

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Determination of MDR1 gene expression for prediction of chemotherapy tolerance and treatment outcome in dogs with lymphoma

Cited by 14 publications

References 30 publications

Mechanisms of Drug Resistance in Veterinary Oncology— A Review with an Emphasis on Canine Lymphoma

Mechanisms of Drug Resistance in Veterinary Oncology— A Review with an Emphasis on Canine Lymphoma

Evaluation of a multi‐agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non‐Hodgkin high‐grade lymphomas

Development of an oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and association between genotypes and chemotherapy side effects

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