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Biomedical subjects

Ryszard Smolarczyk

Publications and source records attributed to Ryszard Smolarczyk.

6 recordsLinked to original sources
PubMed2006

Antitumor effect of RGD-4C-GG-D(KLAKLAK)2 peptide in mouse B16(F10) melanoma model.

Vasculature targeting agents have been tested as cancer therapeutics for the past few years. Such therapy could be accomplished using, for example, bifunctional (two-domain) peptides. RGD-4C-GG-D(KLAKLAK)2, a peptide designed by Ellerby and coworkers (1999) (full sequence: ACDCRGDCFCGGKLAKLAKKLAKLAK), binds selectively to alphaVbeta3 integrin receptors expressed in tumor neovasculature and, after internalization, effectively induces apoptosis of endothelial cells. The aim of this study was to examine if RGD-4C-GG-D(KLAKLAK)2 would efficiently target cells, among them B16(F10), that overexpress alphaVbeta3 receptors, and whether it would be suitable for therapeutic treatment of primary B16(F10) murine melanoma tumors. Thus, the peptide would target two distinct tumor compartments: that formed by endothelium of blood vessels and that made up of neoplastic cells. The therapeutic peptide was recognized and did induce apoptosis in B16(F10) cell line. Tumor growth inhibition was observed following direct intratumoral administration. However, cessation of peptide administration led to rapid tumor growth and death of the animals.

Amino Acid Sequence↗
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↗
PubMed2005

Negligible induction of IFN-gamma, IL-12 and TNF-alpha by DNA-PEI 750 kDa/albumin complexes.

A 750 kDa polyethylenimine (PEI 750 kDa) combined with albumin has been found to mediate in vivo a highly efficient transfection of small amounts of plasmid DNA. Using this exceptional carrier system we evaluated the inflammatory responses triggered by CpG sequences found in plasmid DNA. Using as little as 1 mug DNA transferred in vivo caused an almost negligible response from pro-inflammatory cytokines (IFN-gamma, IL-12 and TNF-alpha), as assessed in serum with a commercially available kit. Administering 750 kDa PEI/albumin/plasmid DNA complexes every three days assured a high and prolonged in vivo expression of a reporter protein. A further increase in the level of such protein was obtained by administering the investigated complexes concurrently with dexamethasone. High gene transfer capability and a relatively low pro-inflammatory response of 750 kDa PEI/albumin/DNA complexes can be exploited for recurrent gene transfer into lungs to treat (via inhalation or instillation) cancer or genetic disorders such as cystic fibrosis.

Albumins↗
PubMed2004

In vivo gene transfer using cetylated polyethylenimine.

UNLABELLED: This report describes gene transfer in vitro as well as in vivo using cetylated low-molecular mass (600 Da) polyethylenimine (28% of amine groups substituted with cetyl moieties), termed CT-PEI. This compound is hydrophobic and has to be incorporated into liposomes in order to be suitable for gene transfer studies. Serum-induced plasmid DNA degradation assay demonstrated that CT-PEI-containing liposomal carriers could protect complexed DNA (probably via condensation). In vitro luciferase gene expression achieved using medium supplemented with 10% serum was comparable to that achieved in serum-reduced medium and was highest for CT-PEI/cholesterol liposomes, followed by CT-PEI/dioleoylphosphatidylcholine liposomes and PEI 600 Da (uncetylated) carrier. In vivo systemic transfer into mice was most efficient when liposome formulations contained CT-PEI and cholesterol. Higher luciferase expression was then observed in lungs than in liver. IN CONCLUSION: liposomes containing cetylated polyethylenimine and cholesterol are a suitable vehicle for investigating systemic plasmid DNA transfer into lungs.

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↗