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P-glycoprotein and outcome in feline lymphoma
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A D VA N C E S
P-GLYCOPROTEIN AND OUTCOME IN FELINE LYMPHOMA Background Hematopoietic tumors comprise about 33% of all feline tumors. Most are malignant lymphoma. Lymphoma is the most chemotherapy-responsive malignancy treated in cats, and combination chemotherapy is considered the treatment of choice. Complete response/remission (CR) rates are significantly lower for cats than in humans and dogs using similar protocols. The CR in cats with treated lymphoma ranges from 47 to 75%. Most patients with a CR to lymphoma will eventually experience a relapse from drug resistance. In dogs, a mechanism of chemotherapy resistance is P-glycoprotein (Pgp). Pgp is a transmembrane protein pump expressed in many tissues, including adrenal gland, kidney, liver, intestine, placenta, blood-brain barrier, lung, peripheral blood bone marrow cells, and multiple fetal cell lines. Overexpression of Pgp is one of the major factors leading to the development of the multidrug resistance (MDR) phenotype in which cancer cells become simultaneously resistant to a variety of different chemotherapeutic agents. Pgp substrates can include vincristine, vinblastine, doxorubicin, mitoxantrone, and corticosteroids. In MDR, these agents may be pumped out of the cells by Pgp. Pgp expression in lymphoma is inversely associated with remission length and survival time. Pgp and MDR have received little attention in cats.
Objectives To evaluate the level of Pgp expression in feline lymphoma and correlate it with clinical outcome.
Procedure Two human Pgp monoclonal antibodies, C219 and C494, were used to detect Pgp expression in tissue samples from 63 cats with lymphoma.
Results Median remission and survival times were 164 and 571 days, respectively. Fourteen cats had positive expression of Pgp using MAb C219, and 40 were positive with C494. Bone marrow involvement, stage,
A D VA N C E S
substage, and use of radiation therapy were significantly associated with survival.
Author Conclusion Pgp expression as assessed by MAb C219 and C494 is not predictive of remission or survival time in cats with lymphoma.
Inclusions Eleven figures, 1 table, 38 references.
Editor Annotation While the authors were successful in demonstrating the presence of Pgp in many of the cat lymphomas they studied, they could not find any correlation with remission duration or survival time. This is unlike people and dogs, where Pgp overexpression is associated with a worse prognosis. There are few reliable prognostic indicators for cats with lymphoma, so the negative finding for Pgp here is disappointing. However, this study is noteworthy because the authors were actually able to identify several other clinically useful factors in this relatively large group of cats. First, cats in this study that had advanced clinical stage of disease, systemic signs of illness (i.e., substage b) or bone marrow involvement had significantly shorter survival items. This means that careful staging is indicated in every cat with lymphoma prior to initiating therapy, including a bone marrow aspirate. Second, aggressive therapy benefitted many cats in this study. Combination radiation and chemotherapy, as well as rescue therapy with the relatively more complex MOPP protocol, resulted in significantly prolonged survival. Based on this, veterinarians managing lymphoma cats with committed owners should not hesitate to offer referral for more intensive anti-cancer therapy when it is indicated. (GEM) Brenn SH, Couto SS, Craft DM, et al. Evaluation of P-glycoprotein expression in feline lymphoma and correlation with clinical outcome. Vet Comp Oncol 2008:6:201-211.
PAG E 7
A D VA N C E S
P-GLYCOPROTEIN AND OUTCOME IN FELINE LYMPHOMA Background Hematopoietic tumors comprise about 33% of all feline tumors. Most are malignant lymphoma. Lymphoma is the most chemotherapy-responsive malignancy treated in cats, and combination chemotherapy is considered the treatment of choice. Complete response/remission (CR) rates are significantly lower for cats than in humans and dogs using similar protocols. The CR in cats with treated lymphoma ranges from 47 to 75%. Most patients with a CR to lymphoma will eventually experience a relapse from drug resistance. In dogs, a mechanism of chemotherapy resistance is P-glycoprotein (Pgp). Pgp is a transmembrane protein pump expressed in many tissues, including adrenal gland, kidney, liver, intestine, placenta, blood-brain barrier, lung, peripheral blood bone marrow cells, and multiple fetal cell lines. Overexpression of Pgp is one of the major factors leading to the development of the multidrug resistance (MDR) phenotype in which cancer cells become simultaneously resistant to a variety of different chemotherapeutic agents. Pgp substrates can include vincristine, vinblastine, doxorubicin, mitoxantrone, and corticosteroids. In MDR, these agents may be pumped out of the cells by Pgp. Pgp expression in lymphoma is inversely associated with remission length and survival time. Pgp and MDR have received little attention in cats.
Objectives To evaluate the level of Pgp expression in feline lymphoma and correlate it with clinical outcome.
Procedure Two human Pgp monoclonal antibodies, C219 and C494, were used to detect Pgp expression in tissue samples from 63 cats with lymphoma.
Results Median remission and survival times were 164 and 571 days, respectively. Fourteen cats had positive expression of Pgp using MAb C219, and 40 were positive with C494. Bone marrow involvement, stage,
A D VA N C E S
substage, and use of radiation therapy were significantly associated with survival.
Author Conclusion Pgp expression as assessed by MAb C219 and C494 is not predictive of remission or survival time in cats with lymphoma.
Inclusions Eleven figures, 1 table, 38 references.
Editor Annotation While the authors were successful in demonstrating the presence of Pgp in many of the cat lymphomas they studied, they could not find any correlation with remission duration or survival time. This is unlike people and dogs, where Pgp overexpression is associated with a worse prognosis. There are few reliable prognostic indicators for cats with lymphoma, so the negative finding for Pgp here is disappointing. However, this study is noteworthy because the authors were actually able to identify several other clinically useful factors in this relatively large group of cats. First, cats in this study that had advanced clinical stage of disease, systemic signs of illness (i.e., substage b) or bone marrow involvement had significantly shorter survival items. This means that careful staging is indicated in every cat with lymphoma prior to initiating therapy, including a bone marrow aspirate. Second, aggressive therapy benefitted many cats in this study. Combination radiation and chemotherapy, as well as rescue therapy with the relatively more complex MOPP protocol, resulted in significantly prolonged survival. Based on this, veterinarians managing lymphoma cats with committed owners should not hesitate to offer referral for more intensive anti-cancer therapy when it is indicated. (GEM) Brenn SH, Couto SS, Craft DM, et al. Evaluation of P-glycoprotein expression in feline lymphoma and correlation with clinical outcome. Vet Comp Oncol 2008:6:201-211.
PAG E 7