Metastatic intranasal mastocytoma in a dog

Background: Mast cell tumors (MCTs) are neoplasms originating from mast cells, which can be well or poorly differentiated. They are considered the most commonly diagnosed malignant cutaneous neoplasm in dogs; however, intranasal forms are still little reported. Thus, this study seeks to report a case of unilateral intranasal MCT exhibiting submandibular lymph node metastasis. Case: A 11-year-old-and-4-month-old dog of undefined breed (UB), weighing 41 kg, was referred to the Veterinary Medical Teaching Hospital of the University of Passo Fundo (UPF), in the state of Rio Grande do Sul, Brazil. Presenting a clinical history of bilateral purulent nasal secretion, accompanied by sneezing in the two months prior to admission, in addition to vomiting and diarrhea. Auxiliary tests were requested, including skull X-ray, cytology of the nasal cavity with a swab, and collection of material from the submandibular lymph node directly through cytology with a needle. Cytological findings from the right nasal cavity were consistent with mast cell tumors (MCTs). Cytological analysis of the left nasal cavity was compatible with dysplasia/cellular reactivity. A heterogeneous population of cells was detected on cytology of the right submandibular lymph node. These findings were consistent with MCT lymph node metastasis. Skull radiography showed an increase in both opacity and soft tissue extension, surpassing the palate, from the canine tooth through the caudal region of the maxillary sinuses to the last molar, without bone destruction. The dog was then admitted for an abdominal ultrasound, which showed no changes in the spleen or liver. The leukocyte count showed mild lymphopenia and the presence of reactive lymphocytes. Through the buffy coat, the presence of rare round cells, compatible with circulating mast cells, was detected. Due to the biological behavior of the neoplasm and its anatomical location, the established therapy was based on the use of vinblastine and prednisolone. The patient did not show any clinical improvements. In a joint decision with the patient's guardian, the dog was euthanized. Discussion: Intranasal MCTs commonly present progressive and intermittent unilateral epitaxis, mucopurulent nasal discharge, dyspnea, and ocular discharge. Several anatomical sites were associated with more aggressive neoplastic phenotypes; those with an unfavorable prognosis were mainly those present in the oral and intranasal mucosa. Cytopathological examination is considered a highly sensitive method for the diagnosis of MCTs. Metastases are present in more than 90% of mucosal MCTs, usually affecting regional lymph nodes and associated with a poor prognosis. Radiography is considered a useful test in determining the size and location of tumors in the nasal cavity. Chemotherapy plays an important role in the treatment, especially in cases like the one described in this report, in which surgical excision is not possible due to the anatomical location of the neoplasm. Intranasal MCTs are uncommon in dogs. In this case, he presented aggressive, metastatic behavior and a poor response to antineoplastic therapy. Furthermore, due to the location of these tumors, they may be clinically similar to a number of other upper respiratory tract diseases, posing a diagnostic challenge. Therefore, it is essential that the search for differential diagnoses be carried out through auxiliary tests, such as cytology and imaging.

Canine mast cell tumour lomustine's sensitization by tyrosine kinase inhibitors

Background: Tyrosine kinase inhibitors (TKIs) may sensitize neoplasms to conventional antineoplastic agents, however such studies are scarse in the veterinary literature and there is no in vivo study about this subject. Although the literature recommend consensual about the use of masitinib for unresectable or metastatic MCTs, the potential of tumour sensitization to chemotherapeutic agents exerted by the drug is poorly explored in veterinary medicine. The objective of this paper was to report, for the first time, the sensitization of 2 canine mast cell tumours (MCTs) to lomustine, with the use of 2 tyrosine kinase inhibitors: masitinib and toceranib. Cases: Two dogs were referred due tumour recurrence in the left pelvic limb (dog 1), and unilateral mass in the right nasal mucocutaneous region (dog 2). The first case was a 8-year-old female Pinscher, and the second case refers to a 8-year-old male mixed-breed dog. Fine needle aspiration of both lesions was performed, and the cytological analysis were compatible with high grade canine MCT. In the first case, it was started a chemotherapeutic treatment with intravenous vinblastine (2 mg/m² ), associated with prednisolone (40 mg/m2 , every 24 h for 7 days), followed by 25 mg/m2 every 24 h, for more 30 days, tramadol (4 mg/kg every 8 h, until new recommendations) and gabapentin (3 mg/kg every 12 h, until new recommendations). However, there was no objective response, and vinblastine was substituted by lomustine (60 mg/m2 every 21 days), however there was also no response after 2 doses. After masitinib importation, the same was started at 12.5 mg/kg orally every 24 h, but there was also no objective response. However, after new lomustine administration the lesion showed complete remission. The second dog initiated its treatment with toceranib, recently licensed in Brazil, at a dosage of 2.7 mg/kg every 48 h, and after 30 days, there was partial remission. However, the remaining lesion still deemed unresectable, and systemic chemotherapy with lomustine (50 mg/m2 ) was initiated along with continuous toceranib. After 3 weeks of the first chemotherapy complete remission was noted and a second dose was administered. Once the patient remained in complete clinical remission, only toceranib was maintained at the same dose. After 11 months using the toceranib, there was sign of disease recurrence and lomustine was re-initiated resulting in complete remission. Discussion: The TKIs masitinib and toceranib might be considered the first-line therapy for unresectable and/or metastatic canine MCT, but also for those cases with confirmed internal tandem duplications in the exon 11 of the c-KIT protooncogene. Masitinib appears to be more selective than others TKI, such as toceranib, imatinib, dasatinib and sunitinib, because it causes weak inhibition of BCR/ABL (breakpoint cluster region-Abelson), Fms (macrophage colony-stimulating factor receptor), Flt-3 (FMS-like tyrosine kinase-3) and VEGFR (vascular endothelial growth factor receptor), which may partially explains its increased safety and lower risk of cardiotoxicity. In the first case, the animal has been treated with lomustine associated to masitinib and showed a progression-free interval of 33 days, however, the response reported may have been lower, due previously exposition to chemotherapeutic agents, which might compromise the response to TKI. The second case, with the association of lomustine and toceranib, was followed up for 365 days, presenting only one recurrence in the final third of the follow-up, however, with subsequent new complete remission. Sensitization of canine MCT to lomustine with TKIs increases the therapeutic possibilities for this neoplasm, mainly in patients with advanced stage and high-grade tumours.

Outcome of adjuvant chemotherapy with lomustine, vinblastine and chlorambucil on management of canine mast cell tumour of high to intermediate risk / Resultado da quimioterapia adjuvante com lomustina, vimblastina e clorambucil no manejo do mastocitoma canino de risco alto a intermediário

In spite of the many available protocols, the use of chemotherapy for the management of canine mast cell tumours (MCT) remains empirical, and there is lack of criteria for the choice of protocol and definition of patients who may benefit from treatment. The objective of this study was to evaluate the outcome of dogs with MCT after adjuvant chemotherapy according to the risk of recurrence or metastasis proposed on the literature. This prospective study included 89 followed up dogs with prognosis assesment including clinical, histological, immunohistochemical and genetic features of canine MCT. Patients were grouped according to risk of recurrence and metastasis and recommended treatment with lomustine followed by chlorambucil if considered at high-risk, or vinblastine followed by chlorambucil if a patient was at intermediate risk. Outcome was defined by disease-free interval (DFI) and overall survival (OS) estimated by Kaplan-Meier curve. Adjuvant lomustine was useful for control of canine MCT of high-risk of recurrence or metastasis, but only when sequentially associated to chlorambucil with a DFI of 686 days and not reached OS. There was no difference in outcome in the intermediate-risk group despite choosen treatment. Patients at intermediate-to-low risk may not require adjuvant treatments, even in the absence of free surgical margins.(AU)

Apesar dos inúmeros protocolos disponíveis, o uso da quimioterapia permanece empírico para o mastocitoma canino e faltam critérios para escolha do protocolo e da definição dos pacientes que poderiam se beneficiar do tratamento. O objetivo deste estudo foi avaliar o resultado de cães com mastocitoma após a quimioterapia adjuvante, de acordo com o risco de recorrência ou metástase proposto na literatura. Este estudo prospectivo incluiu 89 cães com acompanhamento clínico e avaliação prognóstica, incluindo características clínicas, histológicas, imuno-histoquímicas e genéticas dos mastocitomas. Os pacientes foram agrupados segundo o risco de recorrência ou metástase, sendo recomendado tratamento com lomustina seguida de clorambucila, se considerados sob alto risco, ou vimblastina seguida de clorambucila, se estivessem sob risco intermediário. O resultado final foi definido pelo intervalo livre de doença (ILD) e pela sobrevida global (SG), estimados pela curva de Kaplan-Meier. Na adjuvância, a lomustina foi útil no controle do mastocitoma canino de alto risco, mas apenas quando associada ao clorambucila, com um ILD de 686 dias, sem atingir a mediana para SG. Não houve diferença no grupo de risco intermediário, independentemente do tratamento escolhido. Pacientes de risco intermediário podem não necessitar de tratamentos adjuvantes, mesmo na ausência de margens cirúrgicas livres.(AU)

Outcome of adjuvant chemotherapy with lomustine, vinblastine and chlorambucil on management of canine mast cell tumour of high to intermediate risk / Resultado da quimioterapia adjuvante com lomustina, vimblastina e clorambucil no manejo do mastocitoma canino de risco alto a intermediário

In spite of the many available protocols, the use of chemotherapy for the management of canine mast cell tumours (MCT) remains empirical, and there is lack of criteria for the choice of protocol and definition of patients who may benefit from treatment. The objective of this study was to evaluate the outcome of dogs with MCT after adjuvant chemotherapy according to the risk of recurrence or metastasis proposed on the literature. This prospective study included 89 followed up dogs with prognosis assesment including clinical, histological, immunohistochemical and genetic features of canine MCT. Patients were grouped according to risk of recurrence and metastasis and recommended treatment with lomustine followed by chlorambucil if considered at high-risk, or vinblastine followed by chlorambucil if a patient was at intermediate risk. Outcome was defined by disease-free interval (DFI) and overall survival (OS) estimated by Kaplan-Meier curve. Adjuvant lomustine was useful for control of canine MCT of high-risk of recurrence or metastasis, but only when sequentially associated to chlorambucil with a DFI of 686 days and not reached OS. There was no difference in outcome in the intermediate-risk group despite choosen treatment. Patients at intermediate-to-low risk may not require adjuvant treatments, even in the absence of free surgical margins.(AU)

Apesar dos inúmeros protocolos disponíveis, o uso da quimioterapia permanece empírico para o mastocitoma canino e faltam critérios para escolha do protocolo e da definição dos pacientes que poderiam se beneficiar do tratamento. O objetivo deste estudo foi avaliar o resultado de cães com mastocitoma após a quimioterapia adjuvante, de acordo com o risco de recorrência ou metástase proposto na literatura. Este estudo prospectivo incluiu 89 cães com acompanhamento clínico e avaliação prognóstica, incluindo características clínicas, histológicas, imuno-histoquímicas e genéticas dos mastocitomas. Os pacientes foram agrupados segundo o risco de recorrência ou metástase, sendo recomendado tratamento com lomustina seguida de clorambucila, se considerados sob alto risco, ou vimblastina seguida de clorambucila, se estivessem sob risco intermediário. O resultado final foi definido pelo intervalo livre de doença (ILD) e pela sobrevida global (SG), estimados pela curva de Kaplan-Meier. Na adjuvância, a lomustina foi útil no controle do mastocitoma canino de alto risco, mas apenas quando associada ao clorambucila, com um ILD de 686 dias, sem atingir a mediana para SG. Não houve diferença no grupo de risco intermediário, independentemente do tratamento escolhido. Pacientes de risco intermediário podem não necessitar de tratamentos adjuvantes, mesmo na ausência de margens cirúrgicas livres.(AU)

Tratamento de um mastocitoma de alto grau na língua de um cão por meio de radioterapia e quimioterapia: relato de caso / Treatment of a canine high grade lingual mast cell tumor with radiation therapy and chemotherapy: case report

Um canino da raça Boxer, fêmea, de oito anos de idade, foi atendido com salivação, halitose e disfagia. No exame clínico, foi observada uma massa ulcerada no terço médio da língua medindo 3,5 x 4,0cm. A histopatologia e a imuno-histoquímica levaram ao diagnóstico de um mastocitoma de alto grau. O tratamento cirúrgico (glossectomia parcial) foi declinado pelo proprietário, sendo a radioterapia indicada em seu lugar. O protocolo radioterápico empregado foi 15 frações de 300cGy, realizadas cinco vezes por semana. O equipamento utilizado foi de ortovoltagem. A lesão neoplásica apresentou remissão clínica completa a partir da quarta sessão radioterápica. O único efeito colateral observado foi mucosite leve na região irradiada, que, entretanto, não levou a sintomas clínicos. A quimioterapia sistêmica consistiu de vimblastina e lomustina, alternadas a cada 14 dias, durante quatro meses. Até o momento (22 meses após o tratamento), não há evidências de recidiva local ou metástases do mastocitoma. A associação da radioterapia e da quimioterapia pode ser considerada uma alternativa terapêutica nos casos de mastocitomas irressecáveis, já que, neste caso, levou à remissão completa e duradoura de um tumor agressivo, com ótima tolerância do paciente ao tratamento e posterior qualidade de vida.(AU)

An 8 year old female boxer was presented with salivation, halitosis and dysphagia. In the clinical examination, an ulcerated mass in the middle third of the tongue was observed, measuring 3.5 x 4.0cm. Histopathology and immunohistochemistry the confirmed diagnosis of a high-grade mast cell tumor. Surgical treatment (partial glossectomy) was declined by owner, and radiotherapy was indicated. The protocol consisted of fifteen daily fractions of 300 cGy each. The equipment used was an orthovoltage unit. The tumor had complete clinical remission after the fourth session, and mild mucositis was the only side effect observed. Systemic chemotherapy was performed with vinblastine and lomustine, alternated every 14 days, during four months. There is no evidence of local recurrence or metastasis in this patient twenty-two months after treatment. The combination of radiation therapy and chemotherapy can be considered as an alternative therapy in cases of unresectable mast cell tumors. It led to complete and durable remission of an aggressive tumor, with great quality of life.(AU)

Tratamento de um mastocitoma de alto grau na língua de um cão por meio de radioterapia e quimioterapia: relato de caso / Treatment of a canine high grade lingual mast cell tumor with radiation therapy and chemotherapy: case report

Um canino da raça Boxer, fêmea, de oito anos de idade, foi atendido com salivação, halitose e disfagia. No exame clínico, foi observada uma massa ulcerada no terço médio da língua medindo 3,5 x 4,0cm. A histopatologia e a imuno-histoquímica levaram ao diagnóstico de um mastocitoma de alto grau. O tratamento cirúrgico (glossectomia parcial) foi declinado pelo proprietário, sendo a radioterapia indicada em seu lugar. O protocolo radioterápico empregado foi 15 frações de 300cGy, realizadas cinco vezes por semana. O equipamento utilizado foi de ortovoltagem. A lesão neoplásica apresentou remissão clínica completa a partir da quarta sessão radioterápica. O único efeito colateral observado foi mucosite leve na região irradiada, que, entretanto, não levou a sintomas clínicos. A quimioterapia sistêmica consistiu de vimblastina e lomustina, alternadas a cada 14 dias, durante quatro meses. Até o momento (22 meses após o tratamento), não há evidências de recidiva local ou metástases do mastocitoma. A associação da radioterapia e da quimioterapia pode ser considerada uma alternativa terapêutica nos casos de mastocitomas irressecáveis, já que, neste caso, levou à remissão completa e duradoura de um tumor agressivo, com ótima tolerância do paciente ao tratamento e posterior qualidade de vida.(AU)

An 8 year old female boxer was presented with salivation, halitosis and dysphagia. In the clinical examination, an ulcerated mass in the middle third of the tongue was observed, measuring 3.5 x 4.0cm. Histopathology and immunohistochemistry the confirmed diagnosis of a high-grade mast cell tumor. Surgical treatment (partial glossectomy) was declined by owner, and radiotherapy was indicated. The protocol consisted of fifteen daily fractions of 300 cGy each. The equipment used was an orthovoltage unit. The tumor had complete clinical remission after the fourth session, and mild mucositis was the only side effect observed. Systemic chemotherapy was performed with vinblastine and lomustine, alternated every 14 days, during four months. There is no evidence of local recurrence or metastasis in this patient twenty-two months after treatment. The combination of radiation therapy and chemotherapy can be considered as an alternative therapy in cases of unresectable mast cell tumors. It led to complete and durable remission of an aggressive tumor, with great quality of life.(AU)

Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study.

Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.

Administration sous-cutanée de paclitaxel chez des chiens atteints du cancer: une étude préliminaire. Le paclitaxel intraveineux a été sous-utilisé chez les chiens en raison de réactions d'hypersensibilité graves et aiguës. L'administration sous-cutanée (SC) de paclitaxel et son innocuité ne sont pas connues. Dans cette étude préliminaire, l'administration SC de paclitaxel a été évaluée pour des réactions d'hypersensibilité et de toxicité chez 21 chiens atteints d'un cancer avancé. Les chiens ont reçu de 1 à 5 doses de paclitaxel, allant de 85 à 170 mg/m2 SC tous les 14 ou 21 jours. Un total de 40 doses de paclitaxel ont été administrées et aucun des 21 chiens n'a développé de réactions d'hypersensibilité systémique ou locale aiguë. Des lésions cutanées graves au site d'injection se sont développées chez deux chiens après la quatrième injection au même endroit. Une neutropénie de grade 4 a été observée chez 50 % des chiens 5 jours après le premier traitement à 115 mg/m2 (n = 14). Deux animaux ont développé une diarrhée de grade 5 et sont morts probablement à cause d'une insuffisance hémodynamique ou d'une sepsie. Le paclitaxel peut être administré SC chez les chiens sans une réaction d'hypersensibilité.(Traduit par Isabelle Vallières).

Avaliação da mielotoxicidade induzida pelo uso da lomustina (CCNU) em cães durante o tratamento para mastocitoma / Evaluate of the myelotoxicity induced by lomustine (CCNU) in dogs during treatment for mast cell tumor

A lomustina é um agente quimioterápico que vem sendo utilizado no tratamento do mastocitomacanino. Este trabalho tem o objetivo de avaliar os efeitos mielotóxicos induzidos por essa droga duranteo tratamento. Foram avaliados seis cães com mastocitoma utilizando lomustina. Três cães foramtratados de forma adjuvante a cirurgia, sendo dois de grau II e um de grau III e três cães de formapaliativa de grau III. Foram realizados exames clínicos gerais, hemograma completo, dosagem séricade alalino aminotransferase (ALT), fosfatase alcalina, ureia e creatinina. Dois cães apresentaram mielossupressão,com leucopenia e neutrofi lia, na primeira semana após a quimioterapia, retornando aosvalores normais na terceira semana, sem apresentar febre. Foi iniciado antibioticoterapia em ambosos animais e a dosagem posterior de lomustina foi reduzida em 30%. Os demais exames não apresentaramalterações. Os efeitos colaterais do tratamento do mastocitoma com lomustina se mostraramaceitáveis, havendo a necessidade de acompanhamento hematológico e bioquímico desses animais

The lomustine is a chemotherapic agent that has been used in the treatment of canine mast cell tumor.The odd of this paper is evaluate the myelosuppression caused by lomustine in the treatment of Mastcell Tumor (MCT) in dogs. Three dogs were treated with surgery and adjuvante chemotherapy, beingtwo grade II and one grade III and three dogs with grade III were treated with palliative chemotherapy.It was realized haemogram and plasm dosage of alanine aminotransferase, alkaline phosphatase,creatinine and urea. Two dogs presented myelossuppression with leukopenia and neutropenia in thefi rst week after the chemotherapy, returning to the normal value in the third week, without fever. Theboth dogs were treated with antibiotic therapy and the posterior dosage of lomustine was reduced in30%. The others exams didn’t presented any alteration. The adverse effect of the treatment of MCTwith lomustine showed acceptable and the patients have to be monitoring with haematological and biochemistry of these animals

Avaliação da mielotoxicidade induzida pelo uso da lomustina (CCNU) em cães durante o tratamento para mastocitoma / Evaluate of the myelotoxicity induced by lomustine (CCNU) in dogs during treatment for mast cell tumor

A lomustina é um agente quimioterápico que vem sendo utilizado no tratamento do mastocitomacanino. Este trabalho tem o objetivo de avaliar os efeitos mielotóxicos induzidos por essa droga duranteo tratamento. Foram avaliados seis cães com mastocitoma utilizando lomustina. Três cães foramtratados de forma adjuvante a cirurgia, sendo dois de grau II e um de grau III e três cães de formapaliativa de grau III. Foram realizados exames clínicos gerais, hemograma completo, dosagem séricade alalino aminotransferase (ALT), fosfatase alcalina, ureia e creatinina. Dois cães apresentaram mielossupressão,com leucopenia e neutrofi lia, na primeira semana após a quimioterapia, retornando aosvalores normais na terceira semana, sem apresentar febre. Foi iniciado antibioticoterapia em ambosos animais e a dosagem posterior de lomustina foi reduzida em 30%. Os demais exames não apresentaramalterações. Os efeitos colaterais do tratamento do mastocitoma com lomustina se mostraramaceitáveis, havendo a necessidade de acompanhamento hematológico e bioquímico desses animais(AU)

The lomustine is a chemotherapic agent that has been used in the treatment of canine mast cell tumor.The odd of this paper is evaluate the myelosuppression caused by lomustine in the treatment of Mastcell Tumor (MCT) in dogs. Three dogs were treated with surgery and adjuvante chemotherapy, beingtwo grade II and one grade III and three dogs with grade III were treated with palliative chemotherapy.It was realized haemogram and plasm dosage of alanine aminotransferase, alkaline phosphatase,creatinine and urea. Two dogs presented myelossuppression with leukopenia and neutropenia in thefi rst week after the chemotherapy, returning to the normal value in the third week, without fever. Theboth dogs were treated with antibiotic therapy and the posterior dosage of lomustine was reduced in30%. The others exams didnt presented any alteration. The adverse effect of the treatment of MCTwith lomustine showed acceptable and the patients have to be monitoring with haematological and biochemistry of these animals(AU)

Neuropatia paraneoplásica associada ao mastocitoma canino / Paraneoplastic neuropathy associated with canine mast cell tumor

As síndromes paraneoplásicas compreendem um grupo diverso de alterações clínicas associadas a neoplasias e ocorrem em sítios distantes do tumor primário ou de suas metástases. As neuropatias paraneoplásicas são distúrbios raros em cães, mas representam morbidade significativa e servem como importantes indicadores diagnósticos e prognósticos. O presente trabalho relata a ocorrência de dois casos de neuropatia paraneoplásica em cães com mastocitoma, considerando a apresentação clínica, o diagnóstico e as formas de tratamento utilizadas.

Paraneoplastic syndromes comprise a diverse group of clinical anomalies associated with neoplasias and occur in a location distant from the primary tumor or of your metastasis. Paraneoplastic neuropathy are rare disturbs in dogs, but represent significant morbidity and are useful as diagnostic and prognostic indicators. This work report the occurrence of two cases of paraneoplastic neuropathy in dogs with mast cell tumor, considering the clinical signs, diagnosis and treatment used.

Nitric oxide inhibits irreversibly P815 cell proliferation: involvement of potassium channels.

Nitric oxide (NO) has been shown to inhibit both normal and cancer cell proliferation. Potassium channels are involved in cell proliferation and, as NO activates these channels, we investigated the effect of NO on the proliferation of murine mastocytoma cell lines and the putative involvement of potassium channels. NO (in the form of NO donors) caused dose-dependent inhibition of cell proliferation in the P815 cell line inducing growth arrest in the mitosis phase. Incubation with NO donor for 4 or 24 h had a similar inhibitory effect on cell proliferation, indicating that this effect is irreversible. The inhibitory effect of NO was completely prevented by the blockade of voltage- and calcium-dependent potassium channels, but not by blockade of ATP-dependent channels. NO inhibition of cell proliferation was unaffected by guanylate cyclase and by cytoskeleton disruptors. Therefore, NO inhibits cell proliferation irreversibly via a potassium channel-dependent but guanylate cyclase-independent pathway in murine mastocytoma cells.