Tumor microenvironment is one of the major obstacles to the efficacy of chemotherapy in cancer patients. The abnormal blood flow within the tumor results in uneven drug distribution. ...Electrochemotherapy (ECT) is a tumor treatment that adopts the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses having appropriate amplitude and waveforms. This allows the use of lipophobic drugs that frequently have a narrow therapeutic index maintaining at the same time a reduced patient morbidity and preserving appropriate anticancer efficacy. Its use in humans is addressed to the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. On the other hand, in veterinary oncology this approach is gaining popularity, thus becoming a first line treatment for different cancer histotypes, in a variety of clinical conditions due to its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model and reports the new protocols in terms of drugs and therapy combination that have been developed.
BACKGROUND: Advanced carcinoma of the head represents a substantial health problem in cats for local control and overall survival. OBJECTIVES: Evaluate the capability of electrochemotherapy (ECT) to ...improve bleomycin efficacy in cats with periocular carcinoma and advanced carcinoma of the head. ANIMALS: Twenty‐one cats with periocular carcinoma (17 squamous cell carcinoma SCC and 4 anaplastic carcinoma) and 26 cats with advanced SCC of the head. METHODS: Nonrandomized prospective controlled study. Periocular carcinoma cohorts: 12 cats were treated with bleomycin (15 mg/m² IV) coupled with ECT under anesthesia; 9 cats were treated with bleomycin alone. Advanced head SCC cohorts: 14 cats were treated with bleomycin (15 mg/m² IV) coupled with ECT administered under sedation; 12 control cats were treated with bleomycin alone. ECT treatments (2–8) were performed every other week until complete remission (CR) or tumor progression occurred. RESULTS: Toxicities were minimal and mostly treated symptomatically. Overall response rate in the ECT treated animals was 89% (21 Complete Response CR and 2 Partial Response PR) whereas controls had response rate of 33% (4 CR and 3 PR). Median time to progression in ECT group was 30.5 months, whereas in controls it was 3.9 months (P < .0001). Median time to progression for ECT cohorts was 24.2 months for periocular cohort and 20.6 in advanced head SCC cohort, respectively. CONCLUSIONS: Electrochemotherapy is well tolerated for advanced SCC of the head in cats; its use may be considered among loco‐regional strategies for cancer therapy in sensitive body regions such as periocular region.
Proton channels and exchangers in cancer Spugnini, Enrico Pierluigi; Sonveaux, Pierre; Stock, Christian ...
Biochimica et biophysica acta,
10/2015, Letnik:
1848, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Although cancer is characterized by an intratumoral genetic heterogeneity, a totally deranged pH control is a common feature of most cancer histotypes. Major determinants of aberrant pH gradient in ...cancer are proton exchangers and transporters, including V-ATPase, Na+/H+ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs). Thanks to the activity of these proton transporters and exchangers, cancer becomes isolated and/or protected not only from the body reaction against the growing tumor, but also from the vast majority of drugs that when protonated into the acidic tumor microenvironment do not enter into cancer cells. Proton transporters and exchangers represent a key feature tumor cells use to survive in the very hostile microenvironmental conditions that they create and maintain. Detoxifying mechanisms may thus represent both a key survival option and a selection outcome for cells that behave as unicellular microorganisms rather than belonging to an organ, compartment or body. It is, in fact, typical of malignant tumors that, after a clinically measurable yet transient initial response to a therapy, resistant tumor clones emerge and proliferate, thus bursting a more malignant behavior and rapid tumor progression. This review critically presents the background of a novel and efficient approach that aims to fight cancer through blocking or inhibiting well characterized proton exchangers and transporters active in human cancer cells. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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•pH derangement is a common feature of cancers.•Major determinants of aberrant pH gradient in cancer are proton exchangers and transporters.•These includes V-ATPase, Na+/H+ exchanger, MC transporters, CA.•Through proton transporters and exchangers tumors isolate themselves from the body.•Pharmacological inhibition of these molecules may represent the future of cancer therapy.
Background: Electrochemotherapy (ECT) couples the administration of anticancer drugs with the delivery of electric pulses that increase the drug uptake through the cell membranes, resulting in an ...improved efficacy.
Hypothesis: To evaluate the tolerability and efficacy of cisplatin (CDDP) as an ECT agent to prevent recurrence of incompletely resected mast cell tumors (MCTs).
Animals: Thirty‐seven dogs.
Methods: Prospective study recruiting dogs with incompletely excised MCTs as confirmed by surgeon and pathology reports. After debulking, the tumor bed and margins were infiltrated with CDDP, and then exposed to trains of biphasic electrical pulses under sedation. Five minutes after the injection of the chemotherapy agent, sequences of 8 biphasic pulses lasting 50 + 50 μs each, were delivered in bursts of 1,300 V/cm for sclerosed and of 800 V/cm for exposed lesions, with caliper or needle array electrodes, respectively. A second session was performed 1 or 2 weeks later based on clinical considerations.
Results: The treatment was well tolerated with minimal adverse effects. Twenty‐nine dogs had no evidence of recurrence over the 6‐year study period, 6 had tumor recurrence, 1 died of multiple cutaneous MCTs, and 1 died of unrelated causes. The estimated median time to recurrence was 1,200 days. Recurrence was not observed among the long‐term (>1 year) treated dogs.
Conclusions and Clinical Importance: ECT with CDDP appears effective in the treatment of incompletely resected MCT in dogs and could be a useful addition to the current options based on its low cost, limited toxicity, and ease of administration.
A female ferret was referred as an emergency for severe respiratory distress symptoms. At presentation, the patient was listlessness, dyspnoeic, and hyper-responsive. The clinical examination ...evidenced dyspnea with cyanosis, altered cardiac rhythm, and hepatomegaly. Electrocardiography showed an advanced second-degree atrioventricular (AV) block. The liver aspirate was diagnostic for lymphoma. The patient did not respond to supportive therapy and rapidly died. Post-mortem exams confirmed the presence of lymphoma with hepatic involvement. Moreover, a pericardial lymphocytic infiltration and a widespread myocardial nodular localization of lymphoma were evidenced as well. This condition was probably the cause of the cardiac arrhythmia. To the best of our knowledge, ours is the first report of cardiac lymphoma causing heart block in ferrets.
The need for more appropriate animal models in cancer research has led, over the past 20 years, to consider pets with spontaneously occurring neoplasms as a valuable and still under used resource. ...The role of companion animals in the struggle to eradicate cancer can be multiple: they may act as environmental sentinels, help in gaining insights on tumor biology and finally may be enrolled in therapeutic trials which might act as a bridge to the clinic applications. This paper will focus on the most valuable spontaneous neoplasms in companion animals and will analyze the potentials of each histotype as a model for basic research and for new therapeutic strategies. It is conceivable that in the next years comparative oncology will play a paramount role in translational medicine allowing a rapid flow of data from laboratories to clinical application in humans.
An eleven-year-old stallion was referred for adjuvant treatment of an incompletely excised, recurring penile fibrosarcoma. The horse was bright, alert and responsive with a 15 x 12 cm ulcerated ...lesion on the ventral side of the penis. The lesion was the tumor bed of an incompletely excised fibrosarcoma. After complete staging procedures, the owner elected to treat the horse with electrochemotherapy (ECT) using cisplatin as chemotherapy agent. Two sessions of ECT were performed at two-week intervals using local cisplatin followed by trains of biphasic electric pulses applied using different electrodes until complete coverage of the area was achieved. The treatment was well tolerated, and the patient is still disease free after 12 months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in equines carrying soft tissue tumors.
Highlights ► Pregnant mice were exposed to different BPA doses and its concentration in different organs of the offspring measured. ► The exposure time was from day 1 of gestation until the seventh ...day after delivery. ► Examined organs were liver, muscle, hindbrain and forebrain. ► BPA concentration was found dependent on exposure dose and on the offspring gender. ► The biological significance of the results is discussed.
The objectives of this phase I/II study were: i) to determine whether electrochemotherapy (intralesional bleomycin + electric pulses) could be effective in companion animals with different, large ...neoplasms compared to chemotherapy (conventional intralesional bleomycin); ii) to identify potential toxicities; iii) to preliminarily assess the electric field requirements. Twenty-two patients received intralesional bleomycin + administration of permeabilizing electric pulses. Specifically, after the injection of the drug, sequences of 8 biphasic electric pulses lasting 50 + 50 micros each, with 1 ms interpulse intervals, were delivered in bursts of 1300 V/cm for cutaneous and soft tissue lesions, and of 800 V/cm for oral mucosal and exposed soft tissue neoplasms, using caliper electrodes. The treatment was well tolerated and side effects were infrequent. Nevertheless, two previously unreported toxicities (drug-induced vasculitis and pulmonary thromboembolism) have been identified. A high response rate (complete remission + partial remission: > 80%), often long lasting (> 40%) was obtained. Furthermore, results of this trial were compared to a subset of veterinary cancer patients treated with bleomycin single agent, observing a remarkable superiority of the combined treatment (p < 0.01). Altogether, results suggest that electrochemotherapy is a potentially advantageous rescue protocol for bulky, even relapsing neoplasms of companion animals. Further investigations in this field might allow developing improved protocols for the treatment of down-staged relapsing cancer in pets as well as in humans.
A 10-year-old male intact Corso dog was referred for lameness and for a large neoplasm affecting the right foreleg. Physical examination of the patient revealed a 5 x 5 x 3 cm mass in the distal ...right foreleg. Histopathology was consistent with a diagnosis of appendicular osteosarcoma. The staging process found no evidence of metastasis. Because of the large size of the patient, the owners elected to treat their dog with antiresorptive therapy. The patient was treated with an infusion of zoledronic acid every 28 days. The tumour remained stable for 16 months and the lameness of the dog greatly improved. At that time, the patient returned for evaluation of a large rapidly growing prescapular mass. Biopsy confirmed lymph node metastasis and the dog was euthanased. Zoledronic acid showed remarkable palliation in our patient and possibly anti-tumour action and warrants further investigation.
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