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Biomedical subjects

J Hansson

Publications and source records attributed to J Hansson.

At least 109 records · Page 6Linked to original sources
PubMed1989

Dacarbazine versus dacarbazine-vindesine in disseminated malignant melanoma: a randomized phase II study.

In a phase II study 119 patients with disseminated malignant melanoma were randomized to receive treatment with dacarbazine alone or in combination with vindesine. The study was designed to reveal an additive response rate when the drugs were combined. Dacarbazine was given i.v. at 250 mg m-2 per day X V every 4 weeks. In the combination regimen vindesine given at 3 mg m-2 per week was included. One hundred and ten patients were available for evaluation of response. With dacarbazine 4/51 patients obtained a complete remission (8%) and 5/51 patients a partial remission (10%). Overall response rate was 18%. With dacarbazine-vindesine 8/59 patients obtained a complete remission (13%) and 7/59 patients a partial remission (12%). Overall response rate was 25%. The difference in response rates observed between the treatment arms is not statistically significant. Median response duration was 123 days for dacarbazine patients and 171 days for patients receiving dacarbazine-vindesine (difference not statistically significant).

Adult↗
PubMed1988

Effect of D,L-buthionine-S,R-sulfoximine on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic drugs in human melanoma cells.

The effects of D,L-buthionine-S,R-sulfoximine (BSO) on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) were investigated. RPMI 8322 cells were exposed to 0.01 mM BSO for 24 h, which resulted in a decrease in cellular glutathione to 14% without any reduction of cell proliferation or plating efficiency. BSO pretreatment significantly enhanced cytotoxicity of melphalan with a dose modification factor (DMF) of 3.4 and nitrogen mustard (HN2) (DMF 3.3). The increased cytotoxicity was paralleled by similar increases in DNA cross-linking (melphalan: DMF 2.2, HN2: DNF 2.5). A small but significant potentiation by BSO of cis-diamminedichloroplatinum(II) toxicity was seen (DMF 1.5), with a corresponding minor but significant increase in DNA cross-linking (DMF 1.1). Similarly, the potentiation of bis-chloroethylnitrosurea toxicity was small but significant (DMF 1.1), with no significant increase in DNA cross-linking (DMF 1.0). No effect of BSO pretreatment on the rate of removal of HN2-induced DNA cross-links was observed. Thus, the observed sensitization of RPMI 8322 cells to melphalan, HN2, cis-diamminedichloroplatinum(II), and bis-chloroethylnitrosourea was correlated to similar changes in drug-induced DNA cross-linking. Despite the increased cytotoxicity and DNA cross-linking BSO did not significantly increase the intracellular concentration of intact melphalan. These findings support the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets.

Antineoplastic Agents↗
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↗
PubMed1987

Expression of class Pi glutathione transferase in human malignant melanoma cells.

The occurrence of glutathione transferase in human malignant melanoma cell lines and solid tumor material has been analyzed and compared with the enzyme composition in fibroblasts and naevus samples. All cells and tissues investigated contained essentially only the acidic class Pi glutathione transferase as demonstrated by SDS-PAGE and immunoblotting. The enzyme was purified from tumor material and characterized. Its intracellular concentration was significantly higher in all the melanoma cell preparations analyzed than in the non-malignant cells, supporting the view that the class Pi glutathione transferase may contribute to the drug resistance that is characteristic of malignant melanoma.

Breast Neoplasms↗
PubMed1985

Adjuvant chemotherapy of malignant melanoma. A pilot study.

In a pilot study, 26 patients with stage I malignant melanoma, tumor thickness greater than 2.25 mm, and/or Clark level IV, and Stage II tumors were randomized to adjuvant chemotherapy with either DTIC, DTIC/CCNU/vincristine, or to a control group with no further treatment after surgery. The chemotherapy group contained 17 patients and the control group nine patients. The follow-up time is 37-54 months. The recurrence-free and overall survival is significantly longer in the patient group treated with adjuvant chemotherapy as compared to controls (p less than 0.025, according to the log-rank test).

Adult↗
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↗
PubMed1982

Different activities of unscheduled DNA synthesis in human melanoma and bone marrow cells.

Unscheduled DNA synthesis (UDS) indicated by melphalan was studied in freshly collected tumor cells from human melanoma metastases. Comparative studies were done on human bone marrow blast cells. Significant levels of UDS comparable with those in myeloblasts were found in only two of eight melanoma cell populations. This difference between melanoma and blast cells was not related to different cellular uptake of melphalan. When UDS was induced by ultraviolet irradiation, significant levels of UDS were found in all melanoma and blast cell populations studied. Also, in a human melanoma cell line, high levels of UDS were found after exposure to ultraviolet irradiation, while treatment with melphalan did not result in detectable levels of UDS. Possible explanations for the divergent results of UDS in melphalan-exposed melanoma cells are discussed.

Bone Marrow↗
PubMed1982

Flow cytofluorometric DNA analyses of metastases of human malignant melanomas.

Flow cytofluorometric analyses of DNA content were performed on 38 subcutaneous and lymph node metastases from 32 patients with malignant melanoma. Cells from 8 tumors had DNA patterns corresponding to diploid DNA values, and the remaining 30 had aneuploid cell populations, mostly in the diploid to tetraploid region. Eight tumors contained more than one cell population. The number of S-phase cells varied from 3% to 34%. The number of S-phase cells was significantly higher in aneuploid as compared to diploid cell populations. Patients with a proportion of S-phase cells greater than or equal to 10% had a significantly shorter survival time as compared to patients with less than 10% S-phase cells.

DNA, Neoplasm↗
PubMedDate not supplied

Cytotoxicity and DNA cross-linking induced by peptide conjugated m-L-sarcolysin in human melanoma cells.

Peptichemio is a complex of six peptides containing m-L-sarcolysin which is used in cancer chemotherapy. One of the peptides, L-propyl-m-sarcolysyl-L-p-fluorophenylalanine (PSF), is highly toxic to melanoma cells. We have compared the effects of melphalan, m-L-sarcolysin and PSF on human melanoma cell lines. PSF was 35-fold and 28-fold more toxic to RPMI 8322 melanoma cells than melphalan and m-L-sarcolysin, respectively. Similar differences in the cytotoxic effects of PSF and m-L-sarcolysin were also seen with two other melanoma cell lines. The cytotoxicity of both PSF and m-L-sarcolysin to RPMI 8322 melanoma cells was potentiated by depletion of cellular glutathione. Both PSF and m-L-sarcolysin caused a protracted induction of DNA cross-links in RPMI 8322 cells, with maximum at 24 hours after drug exposure. PSF induced 9-fold higher levels of DNA interstrand cross-links than m-L-sarcolysin, indicating that the increased cytotoxicity of this drug is associated with a more efficient induction of DNA damage.

DNA, Neoplasm↗
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

The Ras farnesylation inhibitor BZA-5B increases the resistance to cisplatin in a human melanoma cell line.

Ras proteins have been implicated in transducing cellular responses to DNA damaging agents. We used BZA-5B, an inhibitor of Ras-farnesylation, to examine the role of Ras in cellular sensitivity to cisplatin. A human melanoma cell line (224) with a Gln61Arg mutation in N-ras was used for these studies. We report that BZA-5B treated cells show an increased resistance to cisplatin. BZA-5B treatment decreased the number of cells showing in situ DNA fragmentation and increased cell viability and clonogenic survival after cisplatin treatment. Further experiments showed that cisplatin induction of the immediate early genes c-jun and p21cip1 was not affected by BZA-5B. Finally, we show that cisplatin causes only weak activation of Jun N-terminal kinase (JNK) in a human melanoma cell line. We conclude that inhibition of Ras function decreases the sensitivity of human melanoma cells to cisplatin-induced cell death.

Alkyl and Aryl Transferases↗