Concurrent 5‐fluorouracil and carboplatin for the treatment of canine carcinomas

Menard, K; Flesner, Brian K.; Glahn, Anastasia; Boudreaux, Bonnie; Bryan, Jeffrey N.

doi:10.1111/vco.12426

Cited by 11 publications

(20 citation statements)

References 29 publications

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“…These mechanisms are all thought to play a role in 5-FU cytotoxicity. Previous reports supported the efficacy of 5-FU in the management of canine mammary neoplasia and for various kinds of carcinoma in veterinary medicine [ 20 – 23 ]. However, in dogs 5-FU toxicity (myelosuppression, gastrointestinal toxicity and neurotoxicity) remains a limiting factor [ 24 ].…”

Section: Introductionmentioning

confidence: 80%

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

et al. 2021

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Background 5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5- fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration. Results In three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, non-compartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed. Conclusions Long term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy.

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Section: Introductionmentioning

confidence: 80%

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

et al. 2021

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“…1,3 There is currently a paucity of literature outlining the use of 5-FU in veterinary medicine. 4 Studies have described its use in the treatment of canine mammary and gastrointestinal carcinomas and nasal adenocarcinomas. 1,4,5 5-FU has also been used in horses for the treatment of squamous cell carcinomas.…”

Section: -Fmentioning

confidence: 99%

“…4 Studies have described its use in the treatment of canine mammary and gastrointestinal carcinomas and nasal adenocarcinomas. 1,4,5 5-FU has also been used in horses for the treatment of squamous cell carcinomas. 6 Its use in cats has been discouraged due to neurotoxicity and death.…”

Section: -Fmentioning

confidence: 99%

Transient chemotherapy‐induced alopecia after successful reversal of 5‐fluorouracil myelosuppression and neurotoxicosis in a 9‐month‐old dog

Immelman¹,

Goodman²,

Keller³

2022

Aust Veterinary J

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Background 5‐Fluorouracil (5‐FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5‐FU cream. Case Summary A 9‐month‐old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5‐FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. Conclusion To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5‐FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5‐FU ingestion is possible several hours after the initial event with minimal long‐term consequences.

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“…2 This drug interferes with both DNA replication and RNA synthesis driving cells to death. When applied systemically, 5-FU displays a variety of unwanted side effects 6 that can be avoided by local targeting of the CD/5-FC suicide system.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of the cytosine deaminase::uracil phosphoribosyl transferase/5‐fluorocytosine suicide system for canine melanoma

Glikin

Allende

Finocchiaro

2021

Vet Comparative Oncology

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We tested the efficacy of a yeast cytosine deaminase::uracil phosphoribosyl transferase/5‐fluorocytosine (CDU/5‐FC) non‐viral suicide system on eight established canine melanoma cell lines. Albeit with different degree of sensitivity 5 days after lipofection, this system was significantly efficient killing melanoma cells, being four cell lines highly, two fairly and two not very sensitive to CDU/5‐FC (their respective IC50 ranging from 0.20 to 800 μM 5‐FC). Considering the relatively low lipofection efficiencies, a very strong bystander effect was verified in the eight cell lines: depending on the cell line, this effect accounted for most of the induced cell death (from 70% to 95%). In our assay conditions, we did not find useful interactions either with the herpes simplex thymidine kinase/ganciclovir suicide system (in sequential or simultaneous modality) or with cisplatin and bleomycin chemotherapeutic drugs. Furthermore, only two cell lines displayed limited useful interactions of the CDU/5‐FC either with interferon‐β gene transfer or the proteasome inhibitor bortezomib respectively. These results would preclude a wide use of these combinations. However, the fact that all the tested cells were significantly sensitive to the CDU/5‐FC system encourages further research as a gene therapy tool for local control of canine melanoma.

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Concurrent 5‐fluorouracil and carboplatin for the treatment of canine carcinomas

Cited by 11 publications

References 29 publications

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

Transient chemotherapy‐induced alopecia after successful reversal of 5‐fluorouracil myelosuppression and neurotoxicosis in a 9‐month‐old dog

Therapeutic potential of the cytosine deaminase::uracil phosphoribosyl transferase/5‐fluorocytosine suicide system for canine melanoma

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