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Biomedical subjects

R Lewensohn

Publications and source records attributed to R Lewensohn.

At least 55 records · Page 3Linked to original sources
PubMed1994

Dose intensity of the CAVE regimen in small cell lung cancer correlates to response rate.

Sixty-three patients with limited or extensive small cell lung cancer (SCLC), were treated in the Department of Respiratory Diseases, Huddinge Hospital, between 1985 and 1990, with chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and etoposide (CAVE). The patients were analyzed retrospectively concerning dose intensity (DI) of the chemotherapy actually delivered during induction treatment, the response rate, toxicity and survival. The mean combined relative DI (CRDI) of the induction treatment, consisting of three chemotherapy courses, was 0.7 (projected CRDI = 1.0). The overall response rate was 57% and the median survival time was 291 days. We found a correlation between the combined relative DI (all four drugs together) and the response rate. Increasing the CRDI from the range of 0.28-0.6 to 0.76-0.90 resulted in an increase in the response rate from 35 to 90%. Toxicity was scarce, suggesting that the actual delivered chemotherapy had low intensity. No correlation was found between DI and toxicity or between the response rate and toxicity. A correlation between DI of this induction treatment and survival could not be established. Our findings suggest the utility of reporting the actual DI of chemotherapy trials in SCLC.

Adult↗
PubMed1994

Combined treatment modalities in esophageal cancer. Should chemotherapy be included?

The poor prognosis of esophageal carcinoma patients after treatment with local modalities (surgery/radiotherapy) is well known. The purpose of this review is to assess the question whether addition of chemotherapy to local treatment of squamous cell carcinoma of the esophagus has had any beneficial effect on treatment results. In the absence of a sufficient number of randomized trials addressing this issue, data mainly from single-arm studies are discussed. Compiled data from studies on preoperative chemotherapy, preoperative chemoradiation and chemoradiation without surgery suggest that addition of chemotherapy to local treatment (surgery/radiotherapy) might increase short-term survival (2 years) compared to local therapy alone. In the case of chemoradiation without surgery this conclusion is strengthened by results from randomized trials. In general lack of long-term follow-up data limits conclusion whether to recommend the inclusion of chemotherapy into treatment of esophageal cancer or not. Treatment results, however, from studies utilizing combination chemotherapy given concomitant with radiotherapy support the contention that well-designed randomized trials with long-term follow-up should be performed. Outside controlled trials, however, surgery or radiotherapy should still be regarded as standard treatment modalities.

Carcinoma, Squamous Cell↗
PubMed1994

Less initial rejoining of X-ray-induced DNA double-strand breaks in cells of a small cell (U-1285) compared to a large cell (U-1810) lung carcinoma cell line.

Cells of a small cell lung carcinoma cell line, U-1285, and an undifferentiated large cell lung carcinoma cell line, U-1810, differ in radiosensitivity in parallel to the clinical radiosensitivity of the kind of tumors from which they are derived. The surviving fraction at 2 Gy (SF2) was 0.25 that of U-1285 cells and 0.88 that of U-1810 cells. We investigated the induction of DNA double-strand breaks (DSBs) by X rays and DSB rejoining in these cell lines. To estimate the number of DSBs we used a model adapted for pulsed-field gel electrophoresis (PFGE). The induction levels were of the same magnitude (0.46 and 0.51 DSB/100 Mbp/Gy for U-1810 and U-1285 cells, respectively). These levels of induction do not correlate with radiosensitivity as measured by cell survival assays. Rejoining of DSBs after doses in the range of 0-50 Gy was followed for 0, 15, 30, 60 and 120 min. We found a difference in the velocity of repair during the first hour after irradiation which is parallel to the differences in radiosensitivity. Thus U-1810 cells exhibit a fast component of repair, with about half of the DSBs being rejoined during the first 15 min, whereas U-1285 cells lack such a fast component, with only about 5% of the DSBs being rejoined after the same time. In addition there was a numerical albeit not statistical difference at 120 min, with more residual DSBs in the U-1285 cells compared to the U-1810 cells.

Carcinoma, Large Cell↗
PubMed1993

Pharmacokinetics of peptichemio in myeloma patients: release of m-L-sarcolysin in vivo and in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each of which contains the alkylating residue m-[di(2-chloroethyl)amino]-L-phenylalanine (L-mSL). The fate of PTC was investigated in eight patients with multiple myeloma after intravenous infusion of the drug. The quantitative analysis of the plasma samples was performed by liquid chromatography with fluorometric detection. L-mSL was rapidly released from the peptides and reached its maximal plasma concentration at the end of the infusion. Its median elimination half-life was 1.73 (range, 0.72-2.41) h. It was possible to follow the concentration of only one of the peptides, L-mSL-L-Arg(NO2)-L-Nval.OEt, during and shortly after the infusion of PTC. The stability of L-mSL and the peptides was studied in buffer solution (pH 7.3), plasma, and blood. The stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min. We conclude that L-mSL plays an important role in the mechanism of action of PTC.

Aged↗
PubMed1992

Parathyroid hormone-related peptide, measured by a midmolecule radioimmunoassay, in various hypercalcaemic and normocalcaemic conditions.

The diagnosis of humoral hypercalcaemia of malignancy often presents considerable clinical problems. We have studied parathyroid hormone-related peptide (PTHrP) in serum from patients with humoral hypercalcaemia of malignancy (N = 22), hypercalcaemia of malignancy with skeletal metastases (17), histologically confirmed primary hyperparathyroidism (21) and hypercalcaemic patients with various benign diseases (9). PTHrP measurements were also made in normocalcaemic patients with various malignancies (23), endocrine diseases (13), sarcoidosis (22) and chronic renal failure (17). PTHrP was measured by a novel radioimmunoassay using rabbit antibodies directed towards the midregion of the molecule. Immuno- or silica cartridge extraction of serum before radioimmunoassay enabled us to measure PTHrP in all samples, which may add further information about circulating forms of PTHrP. PTHrP was clearly elevated in patients with humoral hypercalcaemia of malignancy (5.0 +/- 4.7 pmol/l) (mean +/- SD, N = 12) and when the kidney function was impaired (4.0 +/- 0.9 pmol/l) (N = 15) (silica cartridge extraction), whether the subject was hypercalcaemic or not. Some patients with endocrine diseases, including two with primary hyperparathyroidism, had slightly elevated serum PTHrP concentrations, while they were normal in sarcoidosis. In healthy subjects the levels were 1.1 +/- 0.5 pmol/l (N = 15) after immunoextraction and 0.8 +/- 0.2 pmol/l (N = 33) after silica cartridge extraction.

Aged↗
PubMed1991

Efficacy of peptide bound m-L-sarcolysin (peptichemio) on melphalan resistant human myeloma cells in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each containing the alkylating agent m-di(2-chloroethyl)amino-phenylalanine. Freshly obtained myeloma cell infiltrated human bone marrow specimens were in parallel exposed to melphalan and PTC. The cytotoxic effect of the drugs on the myeloma cells of each specimen was measured by the differential staining culture method (DISC). PTC displayed higher cytotoxicity to the myeloma cells as compared to melphalan in all 12 cases analysed. The increase of the cytotoxic effect of PTC compared to melphalan varied between different cases. In melphalan resistant cases the cytotoxic effect of PTC as compared to melphalan was clearly significant (P = 0.001).

Aged↗
PubMed1991

Interphase cell death as related to the cell cycle of melphalan-treated human myeloma cells.

The effect of melphalan on cell loss, cell growth and cell-cycle traverse was studied on the human myeloma cell line RPMI 8226. Melphalan treatment resulted in arrest of cells in late S- and G2-phases in a population of unsynchronized cells. At high concentrations of melphalan (e.g. 40 microM), cell loss was noticed during the first cell cycle after melphalan treatment in addition to the aforementioned arrest of cells in late S and G2. The cell loss after melphalan treatment was further analysed in cells enriched for G1-phase. Cell death in this population of cells occurred between 24 and 48 hr after treatment as the cells were in S and moving over to G2.

Cell Death↗
PubMed1991

Interaction of melphalan and dexamethasone in a human myeloma cell line.

The effects of a combination of melphalan and dexamethasone on cell growth, cell cycle flow, cell loss and DNA cross-links were studied on a myeloma cell line (RPMI 8226). At low concentrations melphalan reduced the cell growth by prolonging the S and G2 stages. Steroid sensitivity of the cell line was characterized by dose-dependent inhibition of cell growth after exposure of up to 1 micron dexamethasone with no cell loss found even at 10-fold saturation concentration. Dexamethasone induced prolongation of all cell cycle phases without any preferences. In combined treatment with melphalan and dexamethasone, inhibition of cell growth was found after 24 h followed by cell loss after 48 h. This cell loss was obtained with concentrations of the drugs which by themselves are only growth inhibitory. Calculation of cell flow showed that cell loss is a delayed process occurring after the cells have left the G1 phase. By alkaline elution it was found that dexamethasone treatment caused an increase in melphalan-induced DNA interstrand crosslinks.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Cell cycle arrest and DNA damage after melphalan treatment of the human myeloma cell line RPMI 8226.

Exposure of a myeloma cell line (RPMI 8226) to a 30-minute pulse of melphalan (1-phenylalanine-mustard) resulted in a cell cycle progression delay characteristic for DNA cross-linking agents. Reduction of outflow of cells from late S- and G2-phases was more pronounced as compared to that from G1-phase. The consequence is a progressive accumulation of cells in late S- and G2-phases. At restoration of outflow of cells from late S- and G2-phases, complete removal of DNA interstrand cross-links, as measured by DNA alkaline elution, was noted. At this time less than 50% of maximum DNA-protein cross-links were removed. Further we found no correlation between restored outflow of cells from the G2-phase and removal of DNA-protein cross-links during the follow-up time of 72 h. No DNA double strand breaks as measured by DNA neutral elution were formed during the observation period. The data suggest that removal of DNA interstrand cross-links seems prerequisite for the outflow of cells from G2 after melphalan treatment.

Cell Cycle↗
PubMed1990

Oral dosage of melphalan and response to treatment in multiple myeloma.

Forty-nine consecutive patients with multiple myeloma were analysed for treatment response in relation to dose of orally administered melphalan (induction therapy). All patients were given at least six courses of melphalan-prednisone. Treatment response, defined as a reduction of the myeloma protein of greater than 50%, was seen in 26 patients while 23 were non-responders. When treatment response was related to the dosage of melphalan given by mg/kg of body weight, the numbers of responding and non-responding patients were similar in the group of patients without dose reduction as well as in that with dose reduction. Drug-induced suppression of white blood cell and platelet count was similar in the responding as well as in the non-responding group indicating that the reason for non-response is not simply explained by deficient drug absorption. When the cumulative dose of melphalan given during the induction therapy was analysed, however, a positive correlation (r = 0.47, P less than 0.001) was seen between the cumulative dose and the degree of response. Thus, the cumulative dose of melphalan given during induction therapy seems to be of importance for the response, but other factors as intrinsic differences in cell sensitivity may also explain the individual responsiveness.

Administration, Oral↗
PubMed1988

Interferon exerts a cytotoxic effect on primary human myeloma cells.

A dye exclusion method was used for testing the sensitivity of primary human myeloma and normal bone-marrow cells to interferon (IFN). Following 4 days of incubation with 5000 units/ml of natural (n) IFN-alpha, there was a greater than 90% decrease in the number of viable myeloma cells in cultures from some patients, whereas myeloma cells from other patients showed intermediate or no sensitivity to IFN. The number of viable non-malignant bone-marrow cells (from the same patients) following a 4-day exposure to nIFN-alpha (5000 units/ml) decreased by 10-60%. Exposure of malignant and non-malignant bone-marrow cells to natural beta- and recombinant alpha- and gamma-IFN, also induced a decrease in the number of viable cells. The decreased number of viable myeloma cells could be observed already after 1 day of exposure to IFN-alpha in vitro. To test whether inhibition of proliferation could account for the observed effects, proliferation, as measured by [3H]thymidine uptake, was studied in some experiments. Only approx. 1-2% of the myeloma cells were labeled with [3H]thymidine during the 4 days of culture in vitro, whereas the proportion of labeled non-malignant cells was approx. 40%. Thus, the IFN-induced reduction of cell number in normal bone-marrow cells could possibly be attributed to a cell multiplication inhibitory effect of IFN, whereas the effect observed in myeloma cells cannot be attributed to cell multiplication inhibition. To test the possibility that the reduction in the number of myeloma cells could be attributed to the activity of autologous cytotoxic T-cells, NK-cells or macrophages, these cells were depleted in some experiments. Depletion of these cells did not, however, influence the IFN-induced decrease in the number of viable myeloma cells. We thus conclude that IFN can reduce the number of viable tumor cells by a cytotoxic effect, unrelated to cell multiplication inhibition.

Aged↗
PubMed1988

Cis-diamminedichloroplatinum(II) toxicity in human melanoma cells and lymphocytes as related to cellular platinum accumulation, DNA cross-linking and inhibition of DNA synthesis.

The cytotoxic effect of cis-diamminedichloroplatinum(II) (cis-DDP), as measured by a dye exclusion assay was much more pronounced in bone marrow cells and phytohemagglutinin (PHA)-stimulated lymphocytes than in a human melanoma cell line. DNA synthesis measured by incorporation of 3H-thymidine was much more sensitive to cis-DDP in PHA-stimulated lymphocytes than in melanoma cells. These differences were not caused by a difference in drug accumulation since measurements of cellular platinum content gave similar results in both cell types. The total amount of DNA cross-links and DNA interstrand cross-links induced by cis-DDP was measured with alkaline elution of DNA. In both PHA-stimulated lymphocytes and melanoma cells low total levels of DNA cross-links and DNA interstrand cross-links were found immediately after drug exposure, followed by a protracted increase in DNA cross-linking for 6-12 hours during further incubation after removal of cis-DDP. The relationship between the concentration of cis-DDP and peak levels of total DNA cross-links as well as DNA interstrand cross-links was linear in both cell types. Cis-DDP was found to induce 5.6 times higher total levels of DNA cross-links 6.1 times higher levels of DNA interstrand cross-links in PHA-stimulated lymphocytes than in melanoma cells. The incorporation of 3H-thymidine was much more reduced in PHA-stimulated lymphocytes than in melanoma cells at similar levels of DNA cross-linking. Thus, both reduced DNA cross-linking and lower effect of DNA cross-links on the DNA synthesis may contribute to the greater resistance of melanoma cells to cis-DDP.

Cell Line↗
PubMed1987

Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells.

The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug. HN2 was considerably more cytotoxic than melphalan as determined by inhibition of colony formation. Immediately following exposure to HN2 maximum levels of DNA cross-links were found. Melphalan, in contrast, caused a protracted induction of DNA cross-links with maximum levels obtained 6-12 h following drug exposure. HN2 induced approximately 13 times higher peak levels of DNA cross-links compared to equal concentrations of melphalan. Removal of DNA cross-links following exposure to both drugs followed an exponential time course. The rate of removal of HN2-induced DNA cross-links was, however, 1.5-2.4 times more rapid than that of melphalan-induced cross-links. A strong correlation was obtained between the cytotoxicity of both drugs and the total area under the curve for DNA interstrand cross-links, indicating that both the initial induction of as well as the rate of removal of DNA interstrand cross-links are important for the cytotoxic effects of bifunctional alkylating agents.

Cell Line↗
PubMed1987

Differential DNA cross-linking and cytotoxicity in PHA-stimulated human lymphocytes exposed to melphalan, m-L-sarcolysin and peptichemio.

DNA interstrand, as well as DNA protein cross-linking, was more efficient in phytohaemagglutinin-stimulated human lymphocytes exposed to m-L-sarcolysin as compared to melphalan at equivalent concentrations of the drug. The cellular uptake of m-L-sarcolysin was more efficient as compared to melphalan. With peptichemio, a mixture of 6 peptides containing m-L-sarcolysin, an intermediate level of DNA cross-linking was found. The differences in DNA cross-linking between the 3 drugs were parallel to differences in cytotoxicity. Peptichemio has been ascribed anti-metabolic properties in addition to the alkylating properties conferred by its m-L-sarcolysin content. In the phytohaemagglutinin-stimulated lymphocytes, however, the effect of peptichemio seems linked to its capacity for DNA cross-linking.

Cell Survival↗
PubMed1983

DNA repair replication, DNA breaks and sister-chromatid exchange in human cells treated with adriamycin in vitro.

The effects of adriamycin (AM) on DNA repair replication, the frequency of sister-chromatid exchange (SCE), the rate of cell proliferation and the frequency of DNA strand breaks were studied in human cells in vitro. No repair replication was observed in lymphocytes exposed to AM in concentrations up to 10(-3) moles/l. DNA repair replication induced by UV and alkylating agents was not affected by a concentration of AM that completely inhibited cell proliferation (10(-6) moles/l). Fibroblasts exposed to AM at 10(-4) moles/l in the presence of hydroxyurea showed an increase of strand breaks and cross-links in DNA. When AM was added to UV-irradiated fibroblasts, there was an increase of DNA strand breaks in addition to the breaks caused by UV alone. Similar effects were observed in lymphocytes. A dose-dependent increase of SCE was observed in lymphocytes exposed to low concentrations of AM (less than 10(-7) moles/l). At higher concentrations the increase of SCE levelled off, and cell proliferation became severely inhibited. There was no evidence of removal of SCE-inducing damage in cells exposed to AM during G0 or G1. The level of SCE induced in the third cell cycle after treatment with AM was not different from that induced during the first two cell cycles. These results suggest that the various genotoxic and cytotoxic effects of AM are caused by different types of cellular damage. Moreover, AM-induced DNA damage persists for several cell cycles in human cells in vitro and seems to be resistant to repair activity.

Cell Cycle↗
PubMed1983

DNA content of human myeloma cells.

DNA flow cytofluorometry of bone marrow cells from 29 patients with multiple myeloma disclosed a 55% incidence of aneuploid cell populations with a DNA index between the diploid and the tetraploid regions (2-4 C) and a mean value of 2.5 C. The bone marrow of these patients demonstrated a correlation between the proportion of aneuploid and morphologically identifiable myeloma cells, which indicates a monoclonal pattern in the aneuploid cases without additional diploid myeloma cell clones. In the present patient material no statistically significant relation was found between diploid and aneuploid cases as regards the type of monoclonal immunoglobulin. Further, there was no difference between the diploid and aneuploid cases as regards myeloma cell differentiation, myeloma cell [3H]-thymidine labeling index or response to melphalan treatment.

Aneuploidy↗