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Biomedical subjects

U Ringborg

Publications and source records attributed to U Ringborg.

At least 55 records · Page 3Linked to original sources
PubMed1996

Genes involved in cell cycle G1 checkpoint control are frequently mutated in human melanoma metastases.

A common characteristic of cancer cells is unrestrained cell division. This may be caused by mutational changes in genes coding for components of cell cycle-controlling networks. Alterations in genes involved in G1 checkpoint control have been registered in many human tumours, and investigations from several laboratories show that such alterations, taken together, are the most frequent changes detected in cancer cells. The present paper describes mutational analysis by polymerase chain reaction-single-strand conformation polymorphism (PCR/SSCP) and nucleotide sequence analysis of the genes coding for the p15, p53 and N-ras proteins in 26 metastases from 25 melanoma patients. The registered mutation frequencies add together with previously registered mutations in p16 in the same patient samples to a substantial total frequency of 44% of patients with mutation in at least one of the investigated genes. These results show the occurrence of heterogeneous defects among components of the cell cycle controlling machinery in a human melanoma tumour sample collection and demonstrate that the total frequency of detected alterations increases with the number of cell cycle controlling genes included in the screening panel.

Carrier Proteins↗
PubMed1996

Mutational analysis of the CDKN2 gene in metastases from patients with cutaneous malignant melanoma.

We analysed 26 metastases from 25 patients with sporadic cutaneous malignant melanoma for alterations in the CDKN2 gene by a combined polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP)/nucleotide sequencing approach. Eleven alterations (one in exon 1, five in exon 2 and five in the 3' non-coding sequence of the exon 3 region) were concordantly and independently detected by both SSCP and nucleotide sequence analysis. Two of the exon 2 changes and the five changes in the non-coding exon 3 region are likely to represent natural polymorphism. Four (15%) of 26 metastases thus had CDKN2 mutations and belonged to 3 (12%) of 25 patients. Semi-quantitative PCR furthermore revealed no sign of homozygous deletions of the CDKN2 exon 2 region. The results support an involvement of the CDKN2 product in the development of a subgroup of sporadic melanomas and encourage the search for alterations in additional genes of the 9p21 region.

Alleles↗
PubMed1996

Inhibition of tumor cell growth by monoterpenes in vitro: evidence of a Ras-independent mechanism of action.

(+)-Limonene (d-limonene) and related monoterpenes show chemopreventive activity against rodent mammary carcinoma and inhibit the growth of cancer cells in vitro. One suggested mechanism for the anti-tumorigenic effect of (+)-limonene is inhibition of the post-translational isoprenylation of growth controlling Ras oncoproteins. We have here examined the growth inhibitory effect of (+)-limonene and other related monoterpenes on PANC-1 pancreas carcinoma cells (carrying a K-ras mutation) and on 12V-H-ras-transformed rat fibroblasts. (+)- and (-)-perillyl alcohol, 7-methyl-perillyl alcohol, (+)-limonene oxide and (+)-perillic acid methyl ester were all found to efficiently inhibit cell growth at 1 mM, whereas (+)-limonene caused an approximately 50% growth reduction at 5 mM. Whereas BZA-5B, an inhibitor of Ras farnesyl transferase, was found to induce morphological reversion of 12V-H-ras-transformed cells, (+)-perillyl alcohol and (+)-limonene did not induce reversion. Furthermore, monoterpenes did not decrease MAP kinase enzyme activity or collagenase promoter activity in PANC-1 cells, two functions known to be down-stream from Ras. We conclude that although effective in inhibiting the growth of tumor cells harboring activated ras oncogenes, limonene and (+)-perillyl alcohol are unlikely to act by inhibiting Ras function.

Alkyl and Aryl Transferases↗
PubMed1996

Prognostic value of serum analyses of S-100 beta protein in malignant melanoma.

S-100 protein was first described in the central nervous system but is also present in malignant melanoma cells. Immunohistochemical detection of S-100 is widely used in the histopathological diagnosis of malignant melanoma. In the present study serum levels of S-100 beta protein were measured in 643 patients with cutaneous malignant melanoma. An immunoradiometric assay with three monoclonal antibodies against bovine S-100 protein beta subunit was used. At the time of blood sampling 553 patients were in clinical stage I, 24 in clinical stage II and 66 in clinical stage III. The overall survival rate was strongly associated with serum levels of S-100 protein. The observed/ expected death ratio was markedly increased with increasing levels of S-100 beta (P < 0.001). A fivefold increase in relative hazard was indicated by a value of S-100 beta exceeding 0.6 microgram/l (P < 0.001) and when this cut-off level was used S-100 beta had additional prognostic value independent of clinical stage (P < 0.001). Our data strongly suggest that S-100 beta in serum is an independent prognostic marker that may be useful in identifying high-risk cases and monitoring response to therapy in patients with malignant melanoma.

Adolescent↗
PubMed1996

Screening for cutaneous malignant melanoma: a feasibility study.

OBJECTIVES: To study two different procedures for inviting subjects to screening for malignant melanoma, and to study the role of specially trained nurses as primary examiners. METHODS: The study was carried out in Stockholm county and comprised 5000 randomly selected men and women aged 40 to 60, of whom 2,500 were invited with a personal invitation letter and with a set time of appointment and 2,500 were sent a questionnaire and instructions for self examination of the skin. To test the nurses' competence, a survey was made, comparing the judgments of skin examination between nurses and doctors. RESULTS: 1654 (66%) of those invited for a skin examination took part. 1507 (60%) replied in the questionnaire group, of whom 1024 (41%) requested and attended a subsequent skin examination. Of the subjects attending from both groups, the nurses judged 9% v 11% as having skin lesions suggesting malignant melanoma, whereas the two doctors referred 4% v 3% of the subjects for surgical biopsy. Two malignant melanomas were detected, both of them in the questionnaire group. In the study of nurses' screening competence, both nurses and doctors equally judged one case out of 19 as having a lesion suspicious for malignant melanoma. CONCLUSIONS: When the questionnaire method was used the results were achieved with one third fewer skin examinations, but it is difficult to conclude whether one of the procedures is better than the other. The results also indicate that nurses can be trained to be the primary examiners in a melanoma screening programme.

Adult↗
PubMed1996

Increased cisplatin sensitivity of human fibroblasts from a subject with inherent glutathione deficiency.

Fibroblasts from an individual with 5-oxoprolinuria are deficient in glutathione (GSH) as compared to cells from a healthy sibling. Glutathione transferase (GST) levels also differ for some isoenzymes: GSH deficient cells have more GST A1-1, but lack GST M1-1. However, the contents of the quantitatively dominating isoenzyme GST P1-1 show no significant difference. While there is equal sensitivity to ultaviolet irradiation (UV), the GSH deficient cells are more sensitive to cisplatin, carboplatin and melphalan. Depletion of GSH with buthionine sulfoximine sensitizes the normal fibroblasts to these drugs. Only slightly more cisplatin-induced DNA cross-links are detected in the GSH deficient cells, and there is no difference in the removal of DNA cross-links. Similar amounts of DNA strand breaks are seen in normal and GSH deficient cells after UV exposure, but there is a reduced rates of resealing of strand breaks in GSH deficient cells. The main conclusion from the studies of these fibroblasts is that GSH plays a significant role in the cellular resistance to cytostatic drugs such as platinum compounds and melphalan.

Cell Line↗
PubMed1995

Psychological reactions in patients with malignant melanoma.

Psychological and psychosomatic reactions to malignant melanoma were studied, comparing patients with tumour thickness < or = 0.8 mm versus > 0.8 mm and recurrent versus non-recurrent patients. Gender differences were also studied. Consecutive melanoma patients, Stage I (n = 144), were interviewed at their first postsurgery follow-up visit to an oncology clinic and completed questionnaires 7 and 13 months later. The questionnaire contained items regarding interest in nevi, sleeping problems, psychosomatic complaints, and the Hospital Anxiety and Depression Scale. Patients with a more unfavourable prognosis (tumour thickness > 0.8 mm), subjected to regular medical procedures, did not differ from those with a more favourable prognosis (< or = 0.8 mm), except reporting more sleeping problems. Women had considerably higher levels of problems than men. Amongst patients with an unfavourable prognosis, those with recurrence within 2 years showed lower levels of anxiety at the first visit compared with those free from recurrence after 2 years.

Adult↗
PubMed1995

Prevalence of primary acquired melanosis and nevi of the conjunctiva and uvea in the dysplastic nevus syndrome. A case-control study.

PURPOSE: To investigate whether conjunctival and uveal nevi and primary acquired melanosis are more common in individuals with the dysplastic nevus syndrome than in control subjects derived from the general population. METHODS: Power calculations were used to determine the sample size. After invitation, 162 individuals with the dysplastic nevus syndrome and 119 control subjects, matched for sex and age but otherwise randomized from the Stockholm county census file, were entered into the study. All individuals were examined in a masked fashion by the same ophthalmologist, and the presence of conjunctival and uveal melanocytic lesions and the iris color, skin type, and hair color of each individual were recorded. Contingency tables and odds ratios were used for statistical evaluation. RESULTS: The proportions of individuals with the dysplastic nevus syndrome featuring primary acquired melanosis of the conjunctiva, or nevi of the iris and choroid were not significantly different from those of control subjects. However, individuals with the dysplastic nevus syndrome appeared to have a more sun-sensitive skin type and a reddish or blond hair color more often than control subjects. CONCLUSION: In contrast to previous reports, this study suggests that ocular melanocytic lesions are no more common in individuals with the dysplastic nevus syndrome than in the general population. Therefore, this work does not provide support that periodic ophthalmic surveillance of individuals with the dysplastic nevus syndrome for the purpose of detecting conjunctival or uveal melanomas, or their precursors, is meaningful.

Adult↗
PubMed1995

O6-methylguanine-DNA methyltransferase activities in biopsies of human melanoma tumours.

Tumour samples obtained from one primary melanoma and several lymph node and skin metastases were analysed for O6-methylguanine-DNA methyltransferase (MGMT) activity. While lymph node and skin metastases had similar average MGMT activity, the variance was significantly higher in lymph node metastases. Variability in MGMT activity was frequently observed in different metastases in the same individual and to a lesser extent within metastases.

Biopsy↗
PubMed1995

The effect of 5-fluorouracil on cisplatin induced DNA interstrand cross-linking in a mouse ascites tumor growing in vivo.

In earlier studies we showed that a supra-additive cytotoxic effect was obtained with combined treatment with cisplatin and 5-fluorouracil (5-FU) of Bp8 ascites tumor growing in vivo in mice. We therefore studied the DNA interstrand cross-linking after single drug treatment with cisplatin, 5-FU and the drugs combined. The alkaline elution technique was used. 5-FU induced no measurable DNA cross-linking. Cisplatin caused a dose-dependent increase in DNA cross-links 6 h after treatment. When combining cisplatin and 5-FU, no significant change in the number of DNA cross-links was found for this time. The removal of DNA interstrand cross-links was studied after 24 and 36 h. There was no difference in the removal rate between single drug treatment with cisplatin as compared with the combined treatment with the two drugs. Also, the number of DNA single strand breaks (SSB) possibly created when the cisplatin induced cross-links or UV-induced DNA damage were repaired were measured with the alkaline elution technique. No increase in the amount of SSB was seen after combined treatment. Thus, we found no interaction of 5-FU and cisplatin in terms of DNA damage. Other mechanisms for the supra-additive effect found when combining cisplatin and 5-FU have to be considered.

Animals↗
PubMed1995

Immunohistochemical analysis of the N-ras p21 and the p53 proteins in naevi, primary tumours and metastases of human cutaneous malignant melanoma: increased immunopositivity in hereditary melanoma.

Immunohistochemical analysis of the N-ras p21 and the p53 proteins was carried out on formalin-fixed sections of naevi, primary melanomas and metastases from patients with sporadic melanoma (SCMM) and with hereditary melanoma (HCMM)/dysplastic naevus syndrome (DNS). Seven out of 11 (64%) common naevi and three out of nine (33%) dysplastic naevi showed increased cytoplasmic N-ras expression. No p53 immunopositivity could be recognized in any of the naevus samples. However, strong N-ras expression as well as immunopositivity for p53 was recognized among primary melanomas and metastases with significantly higher frequency among samples from patients with HCMM compared with samples from SCMM cases (for N-ras, 40% vs 10%, P < 0.01; and for p53 43% vs 17%, P < 0.05). We have earlier registered N-ras codon 61 mutations among metastases from 59% of patients with HCMM and from 24% of subjects with SCMM. A comparison of the genetic data with the immunohistochemical results showed occurrence of increased N-ras p21 expression in the presence and absence of detectable N-ras mutant alleles. Increased expression of wildtype N-ras p21 may contribute to tumorigenicity in the absence of mutational activation, at least in a subset of melanomas. Altogether, N-ras p21 alterations are registered at earlier stages than p53 alterations in melanoma development and may be of aetiological importance, whereas p53 alterations may be associated with tumour progression in the late stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Dysplastic Nevus Syndrome↗
PubMed1995

Tyrosinase activity in the serum of patients with malignant melanoma.

We have recently described a new method for measurement of tyrosinase activity in small amounts of human serum (100 microliters), where the purification of tyrosinase is obtained by adsorption of the enzyme to concanavalin A sepharose. The method, which measures stereospecific dopa oxidation, was used in the winter of 1992-93 for the measurement of activity in serum obtained from 30 healthy subjects and from 10 patients with melanoma metastases. The serum tyrosinase values in the 30 subjects ranged from 0.1 to 1.0 nkatal/l, and the mean value and standard deviation was 0.4 +/- 0.2 nkatal/l. In the 10 patients with melanoma, the tyrosinase serum values ranged from 1.1 to 10.6 nkal/l, and the mean value was 3.1 nkatal/l.

Adult↗
PubMed1995

The expression of glutathione transferase isoenzymes in human malignant lymphoma biopsies.

Glutathione transferase (GST) activity as well as the expression of different classes of GST isoenzymes were studied in 14 lymphoma biopsies. The GST activity measured with 1-chloro-2,4-dinitrobenzene as a substrate, varied almost 9-fold. The expression of GSTs classes Pi, Alpha and Mu was studied by immunoblotting using antibodies against human GSTs. All lymphoma samples displayed high levels of class Pi GST. Class Alpha and Mu GSTs expression varied from not detectable to high. The observations were confirmed by quantitation of the three classes of GST with an ELISA technique. Nine of the patients were treated with bifunctional alkylating agents. A correlation between a clinical complete response to chemotherapy and low expression of GST Alpha was noted (p < 0.02).

Alkylating Agents↗
PubMed1995

Glutathione transferase P1-1 expression in human melanoma metastases: correlation to N-RAS mutations and expression.

Expression of the detoxication enzyme glutathione transferase P1-1 (GST P1-1) at elevated levels has been noted in many types of human tumors, including melanomas. The products of the human H-RAS, K-RAS and N-RAS genes play a key role in intracellular signal transduction leading to transcriptional activation of AP-1 (Fos/Jun) responsive genes. The oncogenic mutated forms of the ras proteins are constitutively active and interfere with normal signal transduction. Mutated RAS genes as well as increased expression of wild-type ras proteins are common features in human tumors including melanoma. We have characterized 30 melanoma metastases from 23 melanoma patients with reference to N-RAS expression and mutation as well as to GST P1 expression (immunohistochemistry and genetic analysis). Twenty-three of 30 samples (70%) had high N-Ras p21 and/or N-RAS codon 61 mutations and 18 of these 23 samples also had high GST P1-1 immunoreactivity. Seven of 30 (23%) samples had low N-Ras p21 immunoreactivity and no detectable N-RAS codon 61 mutations. Six of these 7 samples (86%) also had low GST P1-1 immunoreactivity. The results indicate a statistically significant correlation (Spearman correlation coefficient, r = 0.56, p = 0.001, 2-tailed test) and provide, for the first time, indirect evidence for a possible coregulation of N-RAS and GST P1 in human malignant melanoma which should be further evaluated.

Biomarkers, Tumor↗
PubMed1994

Similar toxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea on lymphocytes from human subjects differing in the expression of glutathione transferase M1-1.

Sixteen healthy donors were investigated for the presence or absence of glutathione transferase (GST) M1-1 in lymphocytes by immunodetection with polyclonal antibodies against human GST M1-1. Nine out of 16 individuals (56%) were categorized as GST M1-1 positive. Phytohaemagglutinin stimulated lymphocytes from GST M1-1 positive and negative donors were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and compared regarding inhibition of [3H]thymidine incorporation as a measure of cytotoxicity. No significant differences in the effect of BCNU were observed between the two groups, indicating that GST M1-1 is not an important resistance factor for BCNU.

Carmustine↗