Biomedical subjects

G Sersa

Publications and source records attributed to G Sersa.

At least 37 records · Page 2Linked to original sources

PubMed1997

Anti-tumor effectiveness of electrochemotherapy with bleomycin is increased by TNF-alpha on SA-1 tumors in mice.

With the aim to increase anti-tumor effectiveness of electrochemotherapy, adjuvant immunotherapy with tumor necrosis factor-alpha (TNF-alpha) was tested on tumors in mice. Increased anti-tumor effectiveness on SA-1 tumors was observed after combining TNF-alpha, injected either intratumorally or peritumorally, with electrochemotherapy using suboptimal dose of bleomycin (BLM). The increased anti-tumor effectiveness was neither the result of potentiated anti-tumor effectiveness of TNF-alpha due to exposure of tumors to electric pulses, nor due to interaction with BLM. Therefore, the effect of adjuvant TNF-alpha treatment might be immunomodulatory, augmenting the anti-tumor activity of electrochemotherapy, and possibly adding a systemic component to the localized electrochemotherapy treatment.

Animals↗

PubMed1997

New TNF-alpha analogues: a powerful but less toxic biological tool against tumours.

Our approach to the modification of recombinant human tumour necrosis factor alpha (rhTNF-alpha) comprised changes in flexible loop regions on the surface of the TNF molecule. Using this approach, two different rhTNF-alpha analogues LK 801 and LK 805 were synthesized and tested for their ability to affect the growth of Sa-1 tumour cells. Results obtained in vitro indicate that neither rhTNF-alpha nor its analogues have a direct cytotoxic effect. In vivo experiments were performed on subcutaneous Sa-1 tumours in A/J mice, where the antitumour effect and the toxic side effects of the cytokines were followed. There was no significant difference between growth delay of tumours in animals treated with native rhTNF-alpha and in animals treated with one of the analogues. On the contrary, the LD50 for rhTNF-alpha was 29.1 microg, for LK 801 59.3 microg, and for LK 805 even 66.1 microg, indicating that LK 801 and especially LK 805 were significantly better tolerated. The results confirm that the rhTNF-alpha molecule has been successfully modified resulting in two new analogues with a potent antitumour activity and much lower systemic toxicity. A particularly low systemic toxicity and a strong antitumour effect were observed after treatment with LK 805 suggesting that this analogue merits further investigation in pre-clinical and clinical trials.

Animals↗

PubMed1997

Determination of platinum in tumour tissues after cisplatin therapy by electrothermal atomic absorption spectrometry.

A simple procedure is described for the determination of platinum in tumours after cisplatin therapy. Tumours were digested in 65% nitric acid by incubation at 37 degrees C for 2 days and platinum analysed under optimum conditions by electrothermal atomic absorption spectrometry with Zeeman background correction. The reproducibility of measurements in general was better than +/- 2%. The calibration graph was linear from 30.0 up to 1000 micrograms l-1 of platinum, while the limit of detection (3 sigma) was found to be 3.0 micrograms l-1 (sample volume 20 microliters). Aqueous standard solutions and the standard addition method were applied in the calibration procedure. Under the recommended analytical conditions, the sample matrix did not influence the determination of platinum significantly. In 72% of samples analysed the differences between results obtained by the two calibration procedures did not exceed +/- 5%.

Animals↗

PubMed1996

Searching for new TNF-alpha analogs having potential application in cancer therapy.

Two new TNF-alpha analogs were prepared and tested for their anti-tumor activity on fibrosarcoma SA-1 tumor model in vivo. In analog LK-801 two histidines (His107His108) were introduced into the surface loop thus enabling efficient purification by metal-affinity chromatography. This analog showed less side effects and can serve as a lead compound to look for other useful mutations. Another analog LK-802 was designed by introduction of additional pair of mutations (Cys95Cys148) into LK-801 in order to prepare disulfide linked TNF trimers. Cytotoxicity on mouse cell line L929 was comparable to TNF-alpha, but effect on tumor growth was quite reduced. Pharmacokinetic study revealed that serum levels of LK-802 were quite low in comparison to native TNF-alpha. This at least partially explains why anti-tumor activity of LK-802 is reduced and also illustrates the problems in designing the analogs with desired in vivo biological properties.

Animals↗

PubMed1996

EPR oximetry: reduction of cell respiration by vinblastine.

Influence of vinblastine (VLB) on the rate of oxygen uptake by HeLa cells was studied using the electron paramagnetic resonance (EPR) method. A suspension of cells was labelled with spin probe 15N PDT. Broadening of the EPR spectrum line widths in the presence of O2 was used to measure its concentration throughout the sample. VLB decreased the rate of O2 consumption, but did not influence the viability of cells at the concentration used (1 ng/ml). In addition, intracellular O2 concentration was measured using a paramagnetic broadening agent CrOX. No significant difference in the intracellular O2 concentration with respect to the extracellular was observed neither in VLB treated nor in untreated cells.

Antineoplastic Agents, Phytogenic↗

PubMed1996

Electrochemotherapy with bleomycin in SA-1 tumor-bearing mice--natural resistance and immune responsiveness.

Electrochemotherapy is an antitumor treatment that utilizes locally delivered electric pulses to increase the effectiveness of chemotherapeutic drugs in cells and tissues. Electric pulses permeabilize tumor cells to allow nonpermeant drugs such as bleomycin to enter the cells. Although preclinical data indicate that immune responsiveness of the organism is important for obtaining cures of the tumors after electrochemotherapy with bleomycin, it is not known how electrochemotherapy affects the immune system of the organism. The aim of the study was to determine the effects of electrochemotherapy with bleomycin on natural resistance and immune responsiveness. Natural resistance was evaluated by phagocytic and intracellular killing activity (oxidative burst) in monocytes and polymorphonuclear granulocytes from venous blood, and immune responsiveness by blast transformation of spleen mononuclear cells to mitogens. The percentage of monocytes in venous blood able to elicit oxidative burst was significantly increased 7 days after the electrochemotherapy and returned to normal values after 14 days. In addition, increased blast transformation of spleen mononuclear cells by stimulation with concanavalin A (T lymphocytes activity) was found 14 days after electrochemotherapy treatment. The results of our study demonstrate that electrochemotherapy with bleomycin affects the immune system of the organism

Animals↗

PubMed1995

Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice.

One of the ways to increase drug delivery into cells and tissues is by a local application of short, intense electric pulses, i.e., electropermeabilization. This approach is used in electrochemotherapy to potentiate antitumor effectiveness of chemotherapeutic drugs. To determine whether electropermeabilization can potentiate antitumor effectiveness of cis-diamminedichloroplatinum(II) (CDDP), electrochemotherapy with CDDP was tested in vitro and in vivo on s.c. SA-1, EAT, and melanoma B16 tumors in mice. Electric pulses were applied to the tumors by percutaneously placed electrodes after i.v. injection of CDDP. Severalfold potentiation of CDDP antitumor effectiveness with electric pulses was obtained, inducing partial or complete responses in tumor growth. Electrochemotherapy was CDDP dose dependent, as well as dependent upon the amplitude of electric pulses. Also important was the sequencing and the interval of CDDP administration, relative to application of electric pulses. Specifically, a good antitumor effect without side effects was obtained with eight electric pulses (electric pulse amplitude, 1040 V; repetition frequency, 1 Hz; pulse width, 100 microseconds; electrode distance, 8 mm; 1300 V/cm) applied 3 min after i.v. injection of 4 mg/kg CDDP. With a higher CDDP dose (8 mg/kg), some long-term complete responses were obtained (14%) on melanoma B16 tumors. Thus, electrochemotherapy with CDDP offers an approach to making chemotherapy with CDDP more effective.

Animals↗

PubMed1994

Effects of vinblastine on cell membrane fluidity and the growth of SA-1 tumor in mice.

Cell membranes can be targets of some anti-cancer drugs. Therefore, the purpose of this study was to determine whether vinblastine (VLB) can also affect the tumor cell membrane. On the in vivo SA-1 tumor model, alteration of cell membrane fluidity (measured by electron paramagnetic resonance, EPR), cytotoxicity and morphological changes of the SA-1 tumor cells after VLB treatment were studied. The cytotoxic effect of VLB was biphasic, with an initial fast increase in cytotoxicity followed by a plateau. The surviving cells had increased membrane fluidity and were morphologically changed. The dose-response curve of VLB on membrane fluidity was also biphasic with an initial fast increase in membrane fluidity followed by a plateau. Since dose-response curves of VLB cytotoxicity and its effect on membrane fluidity were similar, there was a high correlation between both effects. The effect of VLB on membrane fluidity was the most pronounced at 24 h and 48 h after treatment. The results of this study indicate that VLB affects cell membrane by increasing the membrane fluidity of SA-1 tumor cells in vivo in a dose-and time-dependent manner. Therefore, this finding may be beneficially implemented also in priming cells for other cytotoxic drugs and for appropriate timing of drug sequence in combined schedules.

Animals↗

PubMed1994

Interactions of interferon and vinblastine on experimental tumor model melanoma B-16 in vitro.

In this study, we tried to define in vitro interactions of two antitumor agents that have different sites and different mechanisms of action. Vinblastine (VLB) in combination with human recombinant interferon-alpha A/D (rHuIFN-alpha A/D) and in combination with murine recombinant interferon-gamma (rMuIFN-gamma) was studied. The effect of the combination was determined with cell growth kinetics assay on B-16 melanoma and the interaction defined by means of Spector's formula. Both the combination of rHuIFN-alpha A/D with VLB and the combination of rMuIFN-gamma with VLB synergistically inhibited cell growth in vitro. There was a positive biochemical modulation between the two drugs, but it is still unknown whether it occurred at the level of uptake into the cell, metabolism within the cell or egress from the cell.

Animals↗

PubMed1994

Anti-tumor effect of tumor necrosis factor combined with electrotherapy on mouse sarcoma.

Anti-tumor effectiveness of tumor necrosis factor (TNF)-alpha applied peritumorally was assessed in combination with local electrotherapy on subcutaneous SA-1 tumors in mice. TNF and electrotherapy each induced significant tumor growth delay. In combined treatment using TNF and electrotherapy, a synergistic anti-tumor effect was observed, regardless of whether TNF was injected before or after electrotherapy. An extra anti-tumor effect was achieved when TNF in the same total dose (2 x 10(5) U) was split into a priming dose (0.5 x 10(5) U) 1 h before electrotherapy and the other (1.5 x 10(5) U) 24 h thereafter. As the result of this therapeutic combination survival rate of the animals was 40%. No animal survived more than 50 days in groups subjected to TNF or electrotherapy treatment alone. Combined treatment with TNF and electrotherapy induced massive tumor destruction, confirmed by histological examination 2 days after the treatment. The results indicate that TNF and electrotherapy interact and that they can be effective in control of local tumor growth.

Animals↗

PubMed1994

Electric treatment of human melanoma skin lesions with low level direct electric current: an assessment of clinical experience following a preliminary study in five patients.

In this study we have investigated the effects of negative low level direct electric current electrotherapy (current: 1 milliampere; treatment time: 30 minutes) in metastatic or primary melanoma skin lesions. After 12 applications in five patients, tumour regression was observed in all evaluable melanoma skin lesions; four of them were classified as partial responses. This study shows that locally applied electrotherapy with a negative low level direct electric current is an effective treatment that results in reduction of tumour mass of human melanoma skin lesions, and it is possible that it has a positive influence on the course of the metastatically disseminated melanoma. No serious side effects were observed.

Adult↗

PubMed1993

Modification of TNF-alpha pharmacokinetics in SA-1 tumor-bearing mice.

Fibrosarcoma-SA-I-tumor-bearing mice were treated s.c. in the vicinity of tumors (peri-tumorally) or intravenously, with recombinant human TNF-alpha lacking 1 to 3 amino acids from N-terminal part (TNF-alpha Nv3). Tumor growth delay, observed after both routes of TNF-alpha Nv3 application, was statistically significant, though a better anti-tumor effect was achieved after peri-tumoral application. TNF-alpha Nv3 serum levels were determined in these animals and compared with TNF-alpha Nv3 serum levels in healthy animals, which were treated with TNF-alpha Nv3 either s.c. or i.v. The peak serum levels of TNF-alpha Nv3 applied peri-tumorally/s.c. were significantly higher in tumor-bearing than in healthy mice, whereas smaller differences in peak serum levels were found after i.v. application, which might correlate with anti-tumor activity. Whatever the route of application, TNF-alpha Nv3 elimination from the serum of tumor-bearing mice was slower than that in healthy animals. Also, comparison of TNF-alpha Nv3 pharmacokinetic parameters for tumor-free and sarcoma- or melanoma-bearing mice has demonstrated that the pharmacokinetics of TNF-alpha Nv3 are modified in tumor-bearing animals.

Animals↗

PubMed1993

Potentiation of bleomycin antitumor effectiveness by electrotherapy.

Electrotherapy was investigated for its ability to increase the responsiveness of murine tumors to bleomycin treatment. Mice bearing fibrosarcoma were treated with 250 micrograms bleomycin and then with 0.6 mA direct current (DC) for 60 min. Antitumor effects of single treatments were moderate with bleomycin, but significant with electrotherapy. Combined treatment with bleomycin followed by electrotherapy was more effective than either treatment alone. Tumor growth delay of the animals after combined treatment was greater than the summation of tumor growth delays after single treatments. The results of our study indicate that bleomycin and electrotherapy treatments interact, with electrotherapy potentiating the effectiveness of bleomycin treatment.

Animals↗

PubMed1992

The influence of TNF on the membrane fluidity of tumor cells.

Possible TNF (tumor necrosis factor) effects on the membrane fluidity of tumor cells were investigated. Viable tumor cells, TNF sensitive, were obtained from the ascitic form of the SA-1 tumor bearing mice. The influence of in vitro and in vivo treatment of cells with the TNF analog was investigated by EPR (electron paramagnetic resonance). SA-1 cells were spin labeled with the methylester of 5-doxylpalmitate, which primarily dissolves in the membranes. The maximal hyperfine splitting was determined and the empirical correlation time calculated. The results show that TNF significantly decreases the correlation time, i.e. it increases the fluidity of SA-1 cell membranes. Such alteration could contribute to the cytotoxicity of TNF.

Animals↗

PubMed1992

Modified cell proliferation due to electrical currents.

In view of the evidence that electrical currents may enhance healing of chronic wounds and retard tumour growth it is suggested that these currents normalise cell proliferation. Additional support to this contention is given by two reports: one on healing of pressure sores in man and one on tumour growth retardation in mice. The effect of an ionic environment on the cell cycle is analysed. Finally a hypothesis attempting to explain the normalising effect of electrical currents on cell proliferation is proposed. It is known that non-dividing cells, e.g. mature neurons, have high transmembrane potential (TMP) whereas fast-dividing cells, e.g. cancerous cells, have low TMP. When a cell is exposed to an electrical field, one side of the cell becomes hyperpolarised while the opposite side is depolarised. Assuming a nonlinear relationship between TMP and the transmembrane ionic currents, it can be shown that in non-dividing cells their high TMP is lowered; whereas in cells with a high division rate, their low TMP is raised due to cell exposure to the external electrical field. These alterations in transmembrane potential could contribute to the normalisation of abnormal cell proliferation.

Animals↗

PubMed1992

Anti-tumor effect of electrotherapy alone or in combination with interleukin-2 in mice with sarcoma and melanoma tumors.

Electrotherapy with direct current (DC) was performed on two murine tumor models, fibrosarcoma SA-1 and melanoma B16. Three Pt/Ir cathodes were inserted directly into the subcutaneous tumors and two anodes subcutaneously in the vicinity of the tumor. Significant tumor growth delay was achieved after electrotherapy and was dependent on DC intensity (0.6, 1.0, 1.4 and 1.8 mA). Melanoma B16 tumors were more sensitive to electrotherapy than SA-1 tumors. In order to enhance the antitumor effect of electrotherapy, combined treatment with interleukin-2 (IL-2) was performed. When both therapies were combined significant tumor growth delay and also higher curability rate was achieved. The results imply that electrotherapy can be an effective antitumor therapy and that the effects can be enhanced with additional IL-2 therapy.

Animals↗

PubMed1992

Antitumor effect of recombinant human tumor necrosis factor-alpha analog combined with desmuramyl dipeptides LK-409 or LK-410 on sarcoma in mice.

Antitumor effect of recombinant human tumor necrosis factor (TNF)-alpha lacking one to three amino acids from the N terminal part (TNFNv3) was tested for its antitumor effect on subcutaneous fibrosarcoma SA-1 tumors. Peritumoral treatment with 5 x 10(4) U TNFNv3 three times every second day significantly delayed tumor growth. Treatment with 10 times higher dose (5 x 10(5) U) produced 6.0 +/- 1.0 days tumor growth delay, but had side effects such as weight loss. The two new desmuramyl N-acyl dipeptides, LK-409 and LK-410, also exhibited such effect; however, the tumor growth delay was barely significant. The treatment was performed with two concentrations (2.5 micrograms and 25.0 micrograms) applied intraperitoneally for 5 consecutive days, without a dose-dependent effect. Combined treatment with TNFNv3 and desmuramyl dipeptides augmented the antitumor effect of treatments. The effect was additive and significant in the combination of 2.5 micrograms LK-410 with 5 x 10(5) U TNFNv3. LK-410 treatment also reduced the side effects of TNFNv3. The results indicate that combined treatment with both biological response modifiers is effective in tumor treatment.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1990

Inhibition of SA-1 tumor growth in mice by human leukocyte interferon alpha combined with low-level direct current.

A preliminary study of the antitumor effect of partially purified human interferon alpha (IFN-alpha) and low-level direct current (DC) was carried out using a murine subcutaneous SA-1 experimental tumor model. Tumor-bearing animals were treated with 5 x 10(4) IU IFN-alpha peritumorally, or with 0.6 mA DC current for 15 minutes daily, for 6 consecutive days. Antitumor effect was manifested 2 days after the beginning of each treatment modality. Combined treatment with DC current applied immediately after IFN-alpha application was more effective than IFN-alpha treatment alone (P less than 0.005), but not significantly better than DC current treatment (P less than 0.5). The results indicate that the combined treatment with IFN-alpha and DC current can be effective in tumor therapy; however, further work is required to determine optimal scheduling.

Animals↗