Biomedical subjects

Stanislaw Szala

Publications and source records attributed to Stanislaw Szala.

5 recordsLinked to original sources

PubMed2006

Overexpression of heme oxygenase-1 in murine melanoma: increased proliferation and viability of tumor cells, decreased survival of mice.

Heme oxygenase-1 (HO-1), a cytoprotective enzyme, can be induced in tumors in response to anti-cancer therapies. We investigated the role of HO-1 in B16(F10), S91, and Sk-mel188 melanoma cells. Overexpression of HO-1 after transduction with adenoviral vectors increased cell proliferation, resistance to oxidative stress generated by H2O2, and angiogenic potential as determined by induction of endothelial cell divisions. Likewise, cells stably transfected with HO-1 cDNA (B16-HO-1) showed higher proliferation, stress resistance, and angiogenic activity than the wild-type line (B16-WT). HO-1 overexpression in tumors significantly shortened survival of mice after subcutaneous injection of cancer cells (38 and 22 days for B16-WT and B16-HO-1, respectively; P=0.017). This also resulted in development of more packed tumors, with more melanoma cells, and reduced inflammatory edemas. Mice injected with B16-HO-1 had lower levels of tumor necrosis factor and higher serum concentrations of its soluble receptor tumor necrosis factor-RI, whereas tumors overexpressing HO-1 displayed augmented vascularization and stronger production of vascular endothelial growth factor. Finally, B16-HO-1 cells injected intravenously formed more metastases in lungs. Thus, HO-1 overexpression increased viability, proliferation, and angiogenic potential of melanoma cells, augmented metastasis, and decreased survival of tumor-bearing mice, suggesting that induction of HO-1 may be detrimental in anti-cancer therapy of melanoma.

Animals↗

PubMed2004

Two-domain vascular disruptive agents in cancer therapy.

The two-domain vascular drug constructs are selective anti-cancer agents capable of specific targeting and subsequent elimination of endothelial cells lining tumor blood vessels. The destruction of existing vasculature within tumor tissue causes insufficient oxygenation of adjacent neoplastic cells and their necrotic death. The recognition (cognitive) domain of the vascular disruptive agents is responsible for recognizing markers specific for endothelial cells. This domain can be formed by variable regions of antibodies or by suitable ligands (such as those binding various integrin or growth factor receptors). The effector domain, in turn, can be constructed from proteins participating in blood clotting process, as well as from toxins, cytokines, radioactive isotopes or pro-apoptotic factors. This article outlines issues important for constructing such two-domain vascular disruptive agents and emphasizes the modularity of their assembly. Several pharmacokinetic and pharmacodynamic properties of these novel agents are discussed. Compared to known cytostatic substances exerting anti-angiogenic effects, such vascular disruptive agents can be much more effective as cytotoxic agents, especially in combination with proven anti-cancer drugs.

Angiogenesis Inhibitors↗

PubMed2002

Antiangiogenic gene therapy in inhibition of metastasis.

This short review attempts to demonstrate the usefulness of antiangiogenic gene therapy in achieving inhibition of growth in experimentally-induced metastases. Certain normal tissues (for example skeletal muscle) may be used in vivo, after genetic modification, as a "bioreactor", able to produce and secrete into the bloodstream proteins known to exert antiangiogenic effects. By inhibiting neoangiogenesis these proteins would thus prevent the development of metastases. The review discusses also the perspectives of antimetastatic therapy based on certain types of allogenic cells (for example myoblasts and fibroblasts) that had been genetically modified and then microencapsulated. The strategy of encapsulation is aimed at protecting the modified cells secreting antiangiogenic factors from being eliminated by the immune system. Secretion of antiangiogenic proteins by these microencapsulated cells can be controlled with inducible promoters. Antiangiogenic genes remaining under the transcriptional control of such promoters may be switched on and off using antibiotics, such as tetracycline derivatives, or steroid hormones.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Tumour therapy with genes encoding apoptin and E4orf4.

The aim of our study was to investigate whether apoptin and e4orf4 pro-apoptotic genes, transferred by means of electroporation, were suitable for gene therapy of tumours. The two genes were chosen for our study because the proteins they encode induce apoptosis in transformed cells only. The apoptin gene was synthesised based on a published nucleotide sequence. MTT and TUNEL tests confirmed that both the synthesised apoptin gene and the e4orf4 gene indeed induced apoptosis in COS-7, Renca and B16(F10) cell lines. Therapeutic DNA was then administered via electroporation directly into murine B16(F10) tumours. Distinct tumour growth inhibition was seen only during the treatment. The cessation of therapy caused tumour re-growth. Obviously, the efficiency of gene transfer using electroporation is low and did not induce a permanent therapeutic effect.

Animals↗

PubMedDate not supplied

Plasmid DNA-induced cytokines together with cyclophosphamide decrease size and number of melanoma lung metastases.

The aim of this study was to investigate whether the local induction of pro-inflammatory cytokines in mouse lungs would increase the therapeutic effect of cyclophosphamide (CTX) used to treat experimental B16(F10) melanoma lung metastases. CTX shows antiangiogenic properties and inhibits the growth of metastases, albeit without numerical reduction. To destroy small metastases remaining after CTX treatment, pro-inflammatory cytokines were induced by systemically administering plasmid DNA-PEl polyplexes. The CpG sequences present in plasmid DNA are immunostimulatory, i.e. they induce pro-inflammatory cytokines, such as IL-12, TNF-alpha, IFN-gamma and IFN-alpha. The latter has great therapeutic potential as it activates NK cells directly involved in eliminating metastatic foci. Our data indicated, for the first time, that combining cyclophosphamide delivery and local induction of pro-inflammatory cytokines in the lungs with plasmid DNA resulted in reduction in the size of malignant melanoma metastases and their number in mouse lungs. Both effects appeared to contribute to a significant extension of survival.

Animals↗