Biomedical subjects

R Lewensohn

Publications and source records attributed to R Lewensohn.

78 records · Page 5Linked to original sources

PubMedDate not supplied

Increased toxicity and DNA cross-linking by peptide bound m-L-sarcolysin (Peptichemio) as compared to melphalan and m-L-sarcolysin in human melanoma cell lines.

Alteration of the melphalan molecule by shifting the di(2-choroethyl)aminogroup from the para- to the meta-position of the phenylalanine residue results in m-L-sarcolysin. By covalent conjugation of different amino acids at the amino- and carboxylgroups of this molecule, a mixture of six peptides known as Peptichemio has been synthesized. In a previous investigation we found that Peptichemio was less toxic to human lymphoblasts than m-L-sarcolysin. In contrast, in the present investigation we found that Peptichemio has higher cytotoxic effect than m-L-sarcolysin on two human melanoma cell lines. The higher cytotoxicity was paralleled by a higher induction of DNA cross-links by Peptichemio as compared to m-L-sarcolysin. A comparative analysis of the six peptides on Peptichemio showed differences in cytotoxic effects on a melanoma cell line. One of the six peptides displayed a considerably higher cytotoxicity than peptichemio itself.

Cell Line↗

PubMedDate not supplied

Melphalan-induced DNA cross-linking and inhibition of DNA and RNA synthesis in human melanoma and lymphoblast cells.

Melphalan inhibits the incorporation of 3H-thymidine and 3H-uridine significantly more in phytohaemagglutinin (PHA)-stimulated human lymphocytes than in a human melanoma cell line (RPMI 8322). Melphalan - induced total DNA cross-linking was 1.7 times higher and DNA interstrand cross-linking was 1.8 times higher in the PHA-stimulated lymphocytes than in the melanoma cells. A higher level of DNA cross-linking was required in melanoma cells than in PHA-stimulated lymphocytes to obtain similar levels of inhibition of incorporation of 3H-thymidine and 3H-uridine. The outflow of cells from G1 to S phase was significantly more inhibited by melphalan in the lymphocytes than in the melanoma cells. Thus the melanoma cells can replicate and transcribe DNA in the presence of levels of DNA damage, which in PHA-stimulated lymphocytes strongly inhibit DNA and RNA synthesis.

DNA Damage↗

PubMedDate not supplied

Melphalan-induced DNA cross-linking in human melanoma cells and phytohaemagglutinin-stimulated lymphocytes in relation to intracellular drug content and cellular levels of glutathione.

Melphalan-induced DNA cross-linking was compared in a human melanoma cell line (RPMI 8322) and in phytohaemagglutinin (PHA)-stimulated lymphocytes. In both cell types a delayed induction of DNA cross-links was observed, with maximum DNA cross-linking occurring 6-12 hours after drug exposure. Significantly higher peak levels of DNA cross-links were found in PHA-stimulated lymphocytes, total DNA cross-linking being 2.5 times and DNA interstrand cross-linking 2.2 times higher. The intracellular content of free melphalan was 1.3-fold higher in RPMI 8322 cells, thus the lower DNA cross-linking was not due to a lower drug concentration in these cells. RPMI 8322 cells had a 1.8-fold higher level of glutathione, possibly indicating a higher capacity of these cells to inactivate melphalan.

Cell Line↗

PubMedDate not supplied

Different melphalan toxicity and DNA cross-linking in human melanoma cells as compared to phytohaemagglutinin-stimulated lymphocytes.

The cytotoxic effect of melphalan, measured as drug induced inhibition of cellular 3H-thymidine incorporation, was lower in RPMI 8322 melanoma cells than in phytohaemagglutinin-stimulated lymphocytes. Melphalan induced a 1.8-fold higher level of total cross-linking and a 1.5-fold higher level of DNA interstrand cross-linking in the phytohaemagglutinin-stimulated lymphocytes compared to the RPMI 8322 melanoma cells. In addition, higher levels of cross-linking were found in the newly synthesized DNA of lymphocytes in S-phase, as compared to S-phase RPMI 8322 cells. The cellular incorporation of 3H-melphalan was about four times higher in RPMI 8322 cells than in phytohaemagglutinin-stimulated lymphocytes. Thus, the lower toxicity of melphalan in RPMI 8322 cells and the lower levels of melphalan induced DNA cross-linking in these cells is due to intracellular factors rather than a lower cellular uptake of melphalan.

Cell Line↗

PubMedDate not supplied

Characterisation of the G1/S cell cycle checkpoint defect in lung carcinoma cells with different intrinsic radiosensitivities.

Cell cycle perturbations in three lung carcinoma cell lines (U-1285,U1906 and U-1810) with different intrinsic radiosensitivities (SF2 U-1285 = 0.25, SF2 U-1906 = 0.45, SF2 U-1810 = 0.88) were investigated following x-irradiation. Cell cycle flow calculations showed that the G1-->S-phase transit was accelerated in irradiated compared with untreated U-1285 cells, up to 24 hours postirradiation. In U-1810 cells and U-1906 cells the postirradiation G1-->S transit decreased compared with controls. All three cell lines showed no postirradiation induction of p53 and p21CIP1 proteins. Cyclin E was overexpressed and cyclin E-dependent kinase activity was substantially induced by irradiation in U-1285 cells compared with U-1906 and U1810 cells while p27KIP1 was detected at the highest intensity in U-1810 cells and lowest in U-1285 cells. We hypothesise that the accelerated postirradiation G1-->S transit in U-1285 cells is associated with induction of cyclin E-dependent kinase activity and may account for increased radiosensitivity in these cells.

Carcinoma, Non-Small-Cell Lung↗

PubMedDate not supplied

Spontaneous and radiation-induced apoptosis in lung carcinoma cells with different intrinsic radiosensitivities.

Spontaneous and radiation-induced apoptosis in three lung carcinoma cell lines (U-1285, U-1906 and U-1810) with previously characterised intrinsic radiosensitivities (RS) was assessed by TUNEL-staining, detection of DNA laddering and cleavage of poly-(ADP-ribose) polymerase (PARP). Spontaneous apoptosis was detected at a high level in the radiosensitive U-1285, at an intermediate level in U-1906 and not detected in the radioresistant U-1810 cell line. Radiation-induced apoptosis, assessed by TUNEL assay, was present in U-1285 and U-1906 cells but not in U-1810 cells. To explain these findings, expression of Bcl-2, Bax, c-Myc and RB protein and mutations of the p53 gene were analysed. The ratio Bcl-2/Bax was higher in U-1810 cells compared with U-1285 and U-1906 cells. Overexpression of c-Myc and loss of RB was found in U-1285 cells whereas both U-1906 and U-1810 cells expressed RB and showed lower c-Myc expression. Analysis with sequencing of all p53 exons disclosed mutations in all three cell lines. Thus, apoptosis was a p53 independent process in U-1285 and U-1906 cells. RB loss and overexpression of c-Myc may enhance apoptosis in U-1285 cells. Our data suggest that spontaneous apoptosis may correlate with RS in SCLC.

Apoptosis↗