5-fluorouracil: Lifesaving for one species, deadly for others

You're in the middle of a busy day of appointments at your veterinary hospital when you hear the frantic voice of your receptionist paging overhead: “Stat to the lobby! Stat to the lobby!”

You run out to find Mr. Smith, one of your most valued clients, with tears running down his face, holding his seizing teacup Yorkie, Minky, in his arms.

“How long has she been like this, Mr. Smith?” you ask as your technician whisks the seizing dog away to the treatment room.

“About 20 minutes. I tried to get here as fast as I could!” Mr. Smith cries.

“Don't worry, we'll get her stabilized as best as we can,” you reply as you race to the treatment area.

Intravenous catheter placed, you find yourself giving multiple doses of diazepam, then phenobarbital, to no avail. You give a bolus of propofol that finally stops the seizure long enough for you to talk with the client.

“Mr. Smith, what was Minky doing today? Is there anything she could have gotten into?”

Mr. Smith reaches into his pocket and pulls out a chewed tube of topical 5% 5-fluorouracil (5-FU) cream and replies, “Well, I did see that she was chewing on this earlier today, but other than that she was fine. I can't think of anything else that was different today. Please help her! She's all I've got!”

As soon as you see the tube of 5-FU cream, your heart sinks. You realize your chances of being able to help Minky and Mr. Smith today are dismal.

What 5-FU is used for

5-fluorouracil is an antimetabolite chemotherapy agent available in both intravenous and topical formulations for various cancers and precancerous conditions in human medicine. 5-FU acts by binding to and inhibiting thymidylate synthase, which is normally responsible for converting deoxyuridine nucleotides to thymidine nucleotides. The inhibition of thymidylate synthase by 5-FU prevents this conversion, leading to DNA strand breaks and the eventual death of rapidly dividing cells.^1,2

5-FU is commonly used in human medicine to treat dermatological conditions such as epidermal neoplasms (e.g. superficial basal and squamous cell carcinomas), actinic keratosis and vitiligo.2 Use of topical 5-FU in veterinary medicine is limited, primarily due to its toxicity in both dogs and cats, but rare use has been reported for the treatment of ocular neoplasms in dogs and, anecdotally, for actinic keratosis in cats.^3,4 Exposure of dogs and cats to topical 5-FU is usually accidental, and the outcome of such exposure is often death.

Ingestion of topical 5-FU is likely to be fatal in both dogs and cats. In dogs, signs of toxicity can start within 30 minutes of ingestion, with rapid progression to seizures and death within six hours^.5,6 The most common clinical signs following ingestion in dogs include vomiting, tremors, ataxia and seizures.^5,7,8

5-FU toxicity in pets

There are several possible mechanisms of neurotoxicity secondary to the ingestion of 5-FU and buildup of its metabolites. Fluoroacetic acid, a metabolite of 5-FU, inhibits aconitase, an important enzyme involved in the conversion of citrate to isocitrate in the citric acid cycle.⁹ This causes inhibition of the citric acid cycle and thus inhibition of oxaloacetate production. Without oxaloacetate, aspartate cannot be produced either, leading to failure of the urea cycle with consequent toxic hyperammonemia.¹⁰

In addition, 5-FU can prevent the conversion of thiamine to its active form of thiamine phosphate.¹¹ Lack of thiamine phosphate prevents conversion of α-ketoglutarate to succinyl-coenzyme A in the citric acid cycle, again inhibiting production of oxaloacetate and ultimately causing failure of the urea cycle.

Shutdown of the citric acid cycle may also further inhibit the gamma-aminobutyric acid (GABA) shunt, which produces GABA, the primary inhibitory neurotransmitter in the brain, contributing to the development of seizures.^7,9 Histological examinations of the brains of dogs experimentally administered fluoroacetic acid have revealed leukoencephalopathy in the cerebrum due to intramyelin vacuole formation.⁹

Accidental ingestion of 5-FU in pets can occur in many ways. Most commonly, pets chew and puncture the tube containing 5-FU and ingest the medication (Figure 1). Additional means of exposure include licking an owner who has applied the product on themselves as directed by their physician or pharmacist and self-grooming after inappropriate topical application of 5-FU to a pet.5-7 Consumption of more than 43 mg/kg is uniformly fatal in dogs,⁵ but fatalities may occur at doses as low as 2.5 mg/kg.8 In a small patient like Minky, accidental ingestion of just 2 to 3 g of 5% 5-FU cream can be fatal.

Figure 1. A tube of the commonly prescribed topical 5% 5-FU cream used for many human dermatological conditions. Note the teeth marks and puncture in the tube causing the cream to ooze out from a dog chewing on the tube. The cream can be fatal upon accidental ingestion by dogs and cats. (Image courtesy of Rachel Song, VMD, MS, DACVIM (Neurology).)

What can be done

There is no defined effective treatment for 5-FU toxicosis in dogs and cats except palliative therapy aimed at ameliorating clinical signs. If ingestion is detected early, a veterinarian can attempt to induce emesis and then give activated charcoal orally to limit gastrointestinal absorption. Despite aggressive attempts to limit the amount of 5-FU absorbed, patients may still develop significant gastrointestinal signs, including vomiting and diarrhea, due to 5-FU's pronounced activity on rapidly dividing cell lines, such as the epithelial cells of the intestinal crypts.⁶

Unfortunately, intractable seizures that are unresponsive to typical anticonvulsant therapy occur frequently with ingestion of 5-FU. General anesthesia may be necessary to control seizures, and the patient may require mechanical ventilation and management of elevated intracranial pressure.⁷ Treatments directed at reducing hyperammonemia (such as oral or rectal administration of lactulose) and thiamine supplementation may be helpful.

Uridine triacetate can act as a direct antidote for human patients with 5-FU toxicosis, as uridine competitively inhibits cell damage and cell death caused by fluorouracil.¹² However, this drug has not been used successfully in dogs and cats with 5-FU toxicosis and is unlikely to be administered quickly enough in veterinary patients to be effective since death can occur within hours of accidental ingestion.

Raising awareness

Despite how frequently topical 5-FU is prescribed to and used in human patients, it's rare for prescribing doctors and pharmacists to provide information about its severe toxic effects in dogs and cats.¹³ It's up to veterinarians to be well-versed in the drug's toxic effects. It is our responsibility to educate pet owners as well as physicians, pharmacists and even the pharmaceutical companies that produce 5-FU to help prevent further tragic deaths in our beloved dogs and cats.

With approximately 38% of American households owning dogs-totaling a population of 76.8 million-it's obvious that there's a substantial risk of dogs being exposed to 5-FU.¹⁴ It's interesting to note that geographical differences may exist in human use of topical 5-FU, with prescriptions more frequently given in sunny states such as Florida, given the higher rates of certain dermatological conditions in those states. Furthermore, it's been suggested that higher rates of 5-FU toxicosis in dogs and cats may also occur in those same sunny states.⁵

As the large population of baby boomers reaches retirement and many retirees move to destinations with year-round warm, sunny environments, we may see an increase in the exposure of pets to 5-FU. This makes the dissemination of information and education on the toxic effects of topical 5-FU even more crucial in these states to prevent unnecessary deaths of dogs and cats. 

Minky: Case outcome

As for poor Minky, the teacup Yorkshire terrier patient, you estimate based on the size of the tube and the number of punctured areas on the tube from her teeth that she ingested a minimum of 1g of 5% 5-FU. To calculate the total milligrams of 5-FU consumed, convert the percentage of drug per weight of cream into milligrams drug per grams of cream. A 5% concentration of 5-FU contains 50 mg 5-FU per 1g cream. Therefore Minky potentially ingested a minimum of 25 mg/kg dose of 5-FU.

You immediately call poison control, where they tell you the dose is well within the toxic and fatal dose ranges of 5-FU in dogs. Due to her active seizures and now sedated state, you do not think it's safe to decontaminate her stomach. Rather, you send Mr. Smith and Minky immediately to an emergency hospital for further care. Unfortunately, you receive notification from the hospital that Minky was put to sleep after three days of hospitalization because of intractable seizures and hemorrhagic diarrhea.

Consoling a devastated Mr. Smith is one of the hardest things you've ever had to do. Convincing him that he's not at fault for the loss of his beloved companion is even harder, as he sobs on your shoulder, “If only I had known!”

As you hold back your own tears, you look Mr. Smith in the eye and vow to spread awareness of the dangers of this drug to the rest of the medical and veterinary community.

References

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3. Overton TL, Allbaugh RA, Whitley D, et al. A pulse-dose topical 1% 5-fluorouracil treatment regimen in a young dog with corneal squamous cell carcinoma. Vet Ophthalmol 2015;18:350-354.
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14. Burns, K. Pet ownership stable, veterinary care variable. J Am Vet Assoc 2019;254:181-185.