Endoglin is a TGF-beta co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA) molecules against endoglin in vitro and in vivo in human and murine endothelial cells and in vivo in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could be used as an adjunct to the established cytotoxic treatment approaches.
COBISS.SI-ID: 1469819
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
The aim of the study was to evaluate the suitability of the p21 promoter for radiation induced transcriptional targeting with the objective to test the therapeutic effectiveness of the combined radio-gene therapy with p21 promoter driven therapeutic gene interleukin 12. Using the reporter gene experimental models, p21 promoter was proven to be inducible with radiation, the induction was not dose dependent, and it could be re-induced. Furthermore radio-gene therapy with interleukin 12 under control of the p21 promoter had a good antitumor therapeutic effect with the statistically relevant tumor growth delay, which was comparable to that of the same therapy using a constitutive promoter. In this study p21 promoter was proven to be a suitable candidate for radiation induced transcriptional targeting. As a proof of principle the therapeutic value was demonstrated with the radio-inducible interleukin 12 plasmid providing a synergistic antitumor effect to radiotherapy alone, which makes this approach feasible for the combined treatment with radiotherapy.
COBISS.SI-ID: 1643131
The purpose of this systematic review was to consolidate the current knowledge about clinical effectiveness of electrochemotherapy, and to investigate the differences in effectiveness of electrochemotherapy with respect to tumor type, chemotherapeutic drug, and route of drug administration. Data analysis confirmed that electrochemotherapy had significantly higher effectiveness bleomycin or cisplatin alone. The effectiveness was significantly higher for intratumoral than for intravenous administration of bleomycin. Bleomycin and cisplatin administered intratumorally resulted in equal effectiveness of electrochemotherapy. Electrochemotherapy was more effective in sarcoma than in melanoma or carcinoma tumors. The results of this review can be used for prediction of tumor response to electrochemotherapy with respect to various treatment conditions and should be taken into account for further refinement of electrochemotherapy protocols.
COBISS.SI-ID: 9569364
Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Minimal systemic toxicity was observed. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 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