Preliminary Metabolism of Lomustine in Dogs and  Comparative Cytotoxicity of Lomustine and Its Major Metabolites in Canine Cells

Chakkath, Thushara; Lavergne, Sidonie N.; Fan, Timothy M.; Bunick, David; Dirikolu, Levent

doi:10.3390/vetsci1030159

Cited by 8 publications

(7 citation statements)

References 24 publications

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“…In our previous study, we have shown that lomustine and its metabolites showed a time and concentration dependent toxicity in canine lymphoma cell lines 17–71 and GL-1 [ 22 ]. However the canine hepatocytes did not show any detectable cell killing even 6 days after exposure to the drugs.…”

Section: Discussionmentioning

confidence: 99%

“…In our previously published cytotoxicity study [ 22 ], lomustine and its metabolites showed similar degree of cell killing in the canine lymphoid cell lines 17–71 and GL-1, and canine hepatocytes. As alkylation is thought to be the main reason for the cytotoxic effects of these drugs [ 3 ], we wanted to investigate if the compounds have similar pattern of alkylation.…”

Section: Introductionmentioning

confidence: 87%

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Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

Chakkath

Lavergne

Fan

et al. 2015

Veterinary Sciences

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DNA Alkylation is thought to be the reason for the efficacy of lomustine while carbamylation has been implicated as the cause for the side effects seen with lomustine treatment such as hepatotoxicity. In the alkylation study we show that lomustine and its metabolites form similar levels of the DNA adducts N7 hydroxyethylguanine and O6 hydroxyethyldeoxyguanosine. In terms of carbamylation, lomustine showed greater extent of carbamylation in the canine hepatocytes and lymphoma cell lines. The DNA repair enzyme O6 methylguanine DNA methyltransferase (MGMT) causes resistance of tumor cells to bifunctional nitrosourea, like lomustine. There is no data available regarding MGMT expression/activity in canine cells or tissues. Our study shows that there is low MGMT activity in the canine lymphoid cell line 17–71 while the GL-1 cells did not show any detectable enzyme activity or mRNA expression. The MGMT enzyme activity measured in canine hepatocytes is about 250–350 fmol/mg protein as compared to about 90 fmol/mg protein in 17–71 cells. We also show that MGMT mRNA expression in 17–71 cells and canine hepatocytes positively correlates with its enzyme activity in these cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

Chakkath

Lavergne

Fan

et al. 2015

Veterinary Sciences

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“…In one study, T-cell lymphomas actually showed a higher degree of intrinsic drug resistance than B-cell lymphomas (Zandvliet et al, 2015). On the other hand, it is known that alkylating agents are not a substrate of P-glycoprotein efflux mechanisms, and cross resistance is uncommon (Teicher et al, 1986;Borst 2012;Chakkath et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Eerstelijnsbehandeling met CCNU-L(-chloorambucil)-CHOP van honden met een hooggradig multicentrisch of mediastinaal T-cellymfoom

Ossowska¹,

Teske²,

Kuijk³

et al. 2016

Vlaams Diergeneeskundig Tijdschrift

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This retrospective study determined disease free survival (DFS) and progression free survival (PFS) in chemo-naïve dogs with multicentric or cranial mediastinal high-grade T-cell lymphoma, treated with a first-line CCNU-L(-chlorambucil)-CHOP protocol. Of thirteen dogs with multicentric lymphoma, 92.3% achieved a complete remission (CR), and the median DFS and PFS was 317 and 256 days, respectively. Three dogs had cranial mediastinal lymphoma, and achieved a CR with a median DFS and PFS of 978 and 1007 days, respectively. The oneand two-year DFS/PFS probability estimate for dogs with multicentric lymphoma was 0.50/0.46 and 0.42/0.38, respectively, for dogs with cranial mediastinal lymphoma 0.67/0.67. Neutropenia and thrombocytopenia were reported in 52.9% and 50% of the dogs, respectively, while 56.3% experienced grade 1-4 nephrotoxicity, hypothesized to be lomustine-induced. It was concluded that, compared to historical data, the currently described first-line CCNU-L(-chlorambucil)- CHOP protocol could benefit the survival of dogs with multicentric or cranial mediastinal highgrade T-cell lymphoma.

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“…[15] PAC-1 and its derivatives induce apoptosis and are cytotoxic in cell culture to a diverse array of cancer cells, including cell lines derived from white blood cell cancers (lymphoma, [15, 42–51] leukemia, [15, 24, 44, 48–50, 52–55] and multiple myeloma [24, 55]), diverse carcinomas (breast, [15, 44, 48, 49, 52–54, 56–59] renal, [15] adrenal, [15, 60–62] colon, [15, 48, 55, 57–59, 63] lung, [15, 48, 49, 52–59, 63–67] cervical, [44, 55] gastric, [48, 49, 55, 57, 58, 63] ovarian, [55] liver, [48, 49, 55] prostate, [48, 49] and gallbladder [48, 49]), and other solid tumor types (melanoma, [15, 44, 48, 49] osteosarcoma, [55] neuroblastoma, [15, 55, 57, 58] and glioblastoma [48, 49, 68]). Patient-derived samples from colon cancer [15], chronic lymphocytic leukemia [23], and multiple myeloma [24] are also sensitive to PAC-1 and derivatives, and a therapeutic effect has been demonstrated in multiple murine tumor models [15, 48, 49, 56, 65, 66, 69] and in pet dogs with cancer.…”

Section: Pac-1mentioning

confidence: 99%

“…This depletion of the labile zinc pool restores procaspase-3 enzymatic activity, allowing for cleavage of procaspase-3 to caspase-3 and the initiation of the execution pathway of apoptosis. [42] PAC-1 is now widely used as a tool compound for the induction of apoptosis [51, 59, 67, 68, 82, 83], and for the direct activation of procaspase-3 downstream of the mitochondria. [84–87] In addition, multiple independent studies have confirmed the direct procaspase-3 activation mechanism, [48, 85, 88] for example in detailed studies with selective caspase inhibitors, [85] selective caspase substrates, [48] and in Bax/Bak double knockout cells.…”

Section: Pac-1mentioning

confidence: 99%

Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

Roth¹,

Hergenrother

2016

CMC

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PAC-1 induces the activation of procaspase-3 in vitro and in cell culture by chelation of inhibitory labile zinc ions via its ortho-hydroxy-N-acylhydrazone moiety. First reported in 2006, PAC-1 has shown promise in cell culture and animal models of cancer, and a Phase I clinical trial in cancer patients began in March 2015 (NCT02355535). Because of the considerable interest in this compound and a well-defined structure-activity relationship, over 1000 PAC-1 derivatives have been synthesized in an effort to vary pharmacological properties such as potency and pharmacokinetics. This article provides a comprehensive examination of all PAC-1 derivatives reported to date. A survey of PAC-1 derivative libraries is provided, with an in-depth discussion of four derivatives on which extensive studies have been performed.

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Preliminary Metabolism of Lomustine in Dogs and Comparative Cytotoxicity of Lomustine and Its Major Metabolites in Canine Cells

Cited by 8 publications

References 24 publications

Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

Eerstelijnsbehandeling met CCNU-L(-chloorambucil)-CHOP van honden met een hooggradig multicentrisch of mediastinaal T-cellymfoom

Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

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