Electrogene therapy combines administration of plasmid DNA into tissue followed by local application of electric pulses. In electrogene therapy with interleukin-12 (IL-12), different routes of administration, different doses of plasmid DNA and different protocols for delivery of electric pulses were evaluated in numerous preclinical studies. Antitumor effectiveness was tested in different types of primary tumors, distantly growing tumors and induced metastases. Intratumoral IL-12 electrogene therapy has been proved to be very effective in local tumor control, having also a systemic effect. Intramuscular and peritumoral IL-12 electrogene therapy had also a pronounced systemic effect and when combined with other treatment strategies resulted in tumor cures. Antitumor effectiveness of IL-12 electrogene therapy is due to the induction of adaptive immunity and innate resistance and anti-angiogenic action. Translation of preclinical studies into clinical trials in human and veterinary oncology has started with encouraging results that would hopefully lead to further investigation of this therapy, also in combination with other cancer treatment modalities.
COBISS.SI-ID: 980859
Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases. Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan. A 29 metastases in 16 patients were treated by electrochemotherapy. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6-12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue compared to non-treated ones. Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation.
COBISS.SI-ID: 1766267
AMEP (for Antiangiogenic MEtargidin Peptide) is a novel anti-cancer agent exerting anti-proliferative and anti-angiogenic effects by binding to v3 and 51 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoural plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated, one control). At day 1 and day 8, plasmid AMEP was injected intratumourally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and post-treatment biopsies for AMEP mRNA levels by RT-QPCR. Plasmid copy number in blood and urine was determined by QPCR. Minimal systemic toxicity was observed including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma, but not urine. AMEP mRNA was found in 3 of 5 treated lesions and none of control lesions. At day 29, all 5 treated lesions were stable in diameter, whereas 4 of 5 control lesions increased over 20 %. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe, and that local transfection was obtained.
COBISS.SI-ID: 1578363
Application of electric pulses (electroporation –EP) to tissues (muscles and tumors) in vivo has besides the increase of permeability of cell membrane, also blood flow modifying effects, such as changes in the permeability of blood vessels wall for different macromolecules and abrogation of blood flow in tumors. The combination of EP with cytostatic bleomycin (electrochemotherapy – ECT) also has a vascular disrupting effect. We showed that EP and ECT with bleomycin cause an immediate abrogation of blood flow in the tumors, so called vascular lock. The vascular lock is of longer duration in ECT with bleomycin than for EP. We also showed with in vivo real time imaging that ECT with bleomycin has a vascular disrupting effect and that the differences in the response of tumor blood vessels to EP and to ECT with bleomycin are present already within the first hour after the therapy. Moreover, we showed that the normal blood vessels that are surrounding the tumor remain functional after EP as well as after ECT with bleomycin.
COBISS.SI-ID: 1471867
Transdermal drug delivery offers an attractive non-invasive alternative to the conventional delivery methods, such as oral administration and injection. The main advantage of the delivery through skin is the possibility of molecules to enter the circulation, avoiding the metabolic processing of the delivered molecules in the liver. Therefore, the aim of this study was to evaluate electroporation with non-invasive multi-array electrodes, as a delivery method, at different amplitudes of electric pulses (from 70 to 570 V), in order to control the degree of transdermal and topical drug delivery. We developed a new in vivo real-time monitoring system, based on fluorescently labeled molecules, to quantify transdermal and topical delivery. Results obtained with new monitoring system demonstrated that depending on the amplitude of electric pulses, transdermal delivery increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The developed monitoring system was then confirmed and verified by delivering doxorubicin, which was also determined in blood plasma, and fentanyl, which was determined by exploring its effect on mice physiological responses and in blood plasma. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent.
COBISS.SI-ID: 1617019