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Biomedical subjects

N H Mulder

Publications and source records attributed to N H Mulder.

At least 199 records · Page 11Linked to original sources
PubMed1990

A study of human small-cell lung carcinoma (hSCLC) cell lines with different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance.

The cisplatin(CDDP)-resistant cell line GLC4-CDDP shows a variety of differences from the parent line GLC4. The aim of this study was to determine which of the observed changes correlated with the degree of resistance and was therefore relevant to the phenomenon of CDDP resistance. For these experiments we used cells of the sensitive hSCLC cell line GLC4 and the in vitro-acquired CDDP-resistant sublines GLC4-CDDP3 and GLC4-CDDP11, with a resistance factor (RF) of 3 and 11 respectively for CDDP and of 1.8 and 7.4 respectively for carboplatin. Carboplatin was used, in addition to CDDP in seeking relevant mechanisms. No consistency was found between the RF and the growth pattern or antigen expression, cellular volume, doubling time, cellular or nuclear platinum (Pt) content or the level of Pt-non-histone chromatin protein (NHCP) binding. A correlation was found between the RF and the level of glutathione (GSH), and a trend was found for the level of Pt-DNA binding, Pt-GG adduct content and the amount of interstrand cross-links (ISC). These changes might therefore be relevant for the development of resistance. These findings are compatible with a GSH-induced reduction of the amount of reactive Pt in the resistant cell, resulting in a lower net platination and toxic Pt-DNA adduct formation.

Antibodies, Monoclonal↗
PubMed1990

Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin-resistant human small cell lung carcinoma cell line.

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the Mr 170,000 P-glycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed cross-resistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR. Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and m-AMSA-induced DNA cleavage was 5-fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. Therefore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage complex.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Chromosomal damage in peripheral blood lymphocytes of patients treated for testicular cancer.

We describe the presence of a large number of chromosome aberrations in lymphocytes of 50 patients with testicular cancer. These chromosomal aberrations were not only found in patients treated with chemotherapy but also in untreated patients or in patients after surgery alone. Our results suggest a role for genetic instability in the pathogenesis of testicular cancer. This instability might be a risk factor for the development of secondary malignancies.

Adult↗
PubMed1990

Phase II study of carboplatin and cytosine arabinoside in patients with disseminated malignant melanoma.

Twenty-one patients with disseminated malignant melanoma were treated with a combination of carboplatin and cytosine arabinoside. Two complete and three partial remissions occurred. No complete cross-resistance was found with a regimen containing 5-(dimethyltriazeno)imidazole-4-carboxamide (DTIC) in two patients. It is suggested that this regimen might be studied further as a second-line treatment for patients who fail on DTIC-containing treatment.

Adult↗
PubMed1990

Topoisomerases, new targets in cancer chemotherapy.

The enzymes involved in the regulation of the three-dimensional structure of DNA, topoisomerase I and II, are important for the handling of DNA during vital cellular processes such as translation, transcription and mitosis. The enzymes are currently being studied intensively, they are being biochemically characterized and their mechanism of action is now better understood. Empirically discovered antitumor drugs appear to interfere with these enzymes, especially topoisomerase II. The DNA-topoisomerase II complex, which is an intermediate in the normal enzyme pathway, is stabilized by the drug and forms a 'cleavable complex', which appears to be cytotoxic. The drugs involved are, e.g. anthracyclines, epipodophyllotoxins and acridines. The central role of this enzyme offers the cell an opportunity for the development of resistance by down-regulation of this enzyme or the production of resistant mutants, provided the adaptation does not hamper other vital cell functions. Knowledge of the working mechanism and the cellular regulation of the topoisomerases might lead to the selection of most effective drugs and treatment schedules, and to circumvention of drug resistance.

Antineoplastic Agents↗
PubMed1990

Effects of supplemental dietary calcium on the intestinal association of calcium, phosphate, and bile acids.

It has been suggested that supplemental dietary calcium decreases hyperproliferation of colonic epithelial cells because calcium precipitates and thus inactivates luminal bile acids. Therefore, 12 healthy men were studied before and after dietary calcium supplementation (35.5 mmol/day) to quantify intestinal associations of calcium, phosphate, and bile acids. The supplemental dietary calcium was almost completely (95%) recovered, mainly in feces. Calcium increased the fecal excretion of both phosphate (31%) and bile acids (53%) and decreased the ratio of dihydroxy to trihydroxy bile acids in duodenal bile almost twofold. In vitro studies showed that precipitation of glycodeoxycholic acid was caused by the formation of insoluble calcium phosphate. Water-soluble and calcium-associated amounts of phosphate and bile acids in feces were measured by resolubilization studies, using the calcium chelator ethylenediaminetetraacetate. In both the control and calcium periods, significant amounts of phosphate (80% and 90%) and bile acids (33% and 50%) were calcium-associated. Moreover, the calcium-induced increments in fecal phosphate and bile acids were completely calcium-associated. Calcium decreased the amount of water-soluble phosphate but not of bile acids. These results indicate that supplemental calcium stimulates formation of insoluble calcium phosphate in the intestinal lumen and thus increases binding of luminal bile acids.

Bile Acids and Salts↗
PubMed1990

Modification of 5-fluorouracil activity by high-dose methotrexate or leucovorin in advanced colorectal carcinoma.

21 patients with advanced colorectal carcinoma were entered into a phase II study to evaluate efficacy and toxicity of methotrexate (MTX), 1500 mg/m2 rapid infusion on day 1, combined with continuous infusion of 5-fluorouracil (5-FU), 600 mg/m2 per 24 h on days 1-4. 12 patients who had progressive disease during this regimen subsequently received high-dose leucovorin, 200 mg/m2 bolus injection on days 1-4, combined with 4 days' continuous infusion of 5-FU. In the MTX/5-FU group 1 pathologically proven complete remission and 3 partial remissions were seen (response rate 20%). The median progression-free interval was 30 weeks. In 12 patients with progressive disease leucovorin/5-FU stabilized disease in 2 (17%). Toxicity in both regimens was tolerable, gastro-intestinal side-effects being most frequent. There were no treatment-related deaths. Median survival time was 10 months. Serum levels of carcinoembryonic antigen before treatment or doubling-time during progression did not correlate with survival.

Adult↗
PubMed1990

Risks and benefits of cisplatin in ovarian cancer. A quality-adjusted survival analysis.

Both the efficacy and toxicity of short intensive cisplatin-based chemotherapy was established in an unselected group of patients with stage III-IV ovarian cancer. The impact of this treatment on quality of life (QOL) was assessed by the TWIST index, expressed as Time Without Symptoms of Treatment and Disease, in relation to the individual length of progression free survival (PFS). Sixty-eight patients were treated with six cycles of a combination of cyclophosphamide, Adriamycin and cisplatin (CAP-5), every 4 weeks. Patients with a clinical response to treatment were evaluated by second look laparotomy (SLL), which could be performed in 52 patients. There were 20 pathological CR, seven microscopic disease, 17 PR and eight SD in these 52 patients. Median follow up at evaluation was 22 months. The median progression free survival (PFS) was 18 months and the median overall survival 22 months. The median duration of TWIST was 10 months, indicating that about 8 months were lost to symptoms due to treatment or hospital admissions for chemotherapy or laparotomy. Of 45 patients receiving six cycles, only eight patients had no symptoms of peripheral neuropathy, and four patients were free of nephropathy at the end of treatment. The overall survival for this limited duration of treatment is similar to that after more protracted treatment. Despite its limited duration, however, about 28% of the cumulative period of progression free survival is consumed by the treatment and its side-effects. Correction of PFS by TWIST may be a suitable instrument to compare the impact of different cytotoxic schedules on quality of life.

Adult↗
PubMed1990

Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer.

Twenty evaluable patients with minimal residual ovarian cancer at second look laparotomy were treated with human recombinant interferon alpha-2b (IFN) intraperitoneally. The dose administered was 50 x 10(6) units once weekly for 8 weeks. Seventeen patients were evaluated by a relaparotomy: five had a pathological complete remission, four a partial response, six patients disease stabilization and two patients had progression. Three patients, two stable and one with clinical progression, had no laparotomy. Nine of the 11 patients with residual tumor smaller than 5 mm had a response, while no response was found in six patients with residuals over 5 mm. The median duration of CR is 11+ months (6-13+ months) after evaluation. For toxicity, 156 treatment cycles could be studied. Fever was seen in 80% of all cycles within 24 h following administration of IFN, in 58 cycles (37%) over 38 degrees C and in 65 cycles (43%) over 39 degrees C. Abdominal pain was slight in 32% and moderate in 3% of all cycles. The peripheral blood leukocyte counts dropped after 52% of all cycles, in 27% below 4.0, in 22% below 3.0, and in one patient below 2.0 x 10(9)/l. IFN dosage was not reduced for leukopenia, but in one patient reduction was necessary for thrombopenia, resulting from insufficient marrow reserve after a previous autologous bone marrow transfusion. Pharmacokinetic studies showed i.p. IFN levels 50-100 times the blood levels. Blood levels were still elevated 2 days after i.p. infusion, but normalized within 1 week on repeated administration. At the second instillation, lower peak serum levels were reached. In conclusion, high doses of i.p. IFN appear to be active in patients with minimal residual disease, with ongoing response in CR patients. Apart from general malaise on the day of treatment, toxicity was acceptable. IFN may be active in patients with minimal residual ovarian cancer through local as well as systemic effects.

Adult↗
PubMed1990

Pharmacokinetics of carboplatin at a dose of 750 mg m-2 divided over three consecutive days.

Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.

Adult↗
PubMed1990

The formation and removal of cisplatin (CDDP) induced DNA adducts in a CDDP sensitive and resistant human small cell lung carcinoma (HSCLC) cell line.

In DNA digested samples of CDDP sensitive (GLC4) and an 11-fold resistant (GLC4-CDDP) hSCLC line, the CDDP induced DNA adducts Pt-GG (Pt-(NH3)2d (pGpG], Pt-AG (Pt-(NH3)2d (pApG], G-Pt-G (Pt-(NH3)2d (GMP)2) and Pt-GMP (Pt-(NH3)3d GMP), were measured with polyclonal antibodies. The total amount of platinum (Pt) bound to DNA was also measured but with the help of atomic absorption spectroscopy (AAS). An increased net formation in GLC4 compared with GLC4-CDDP is found for the total Pt bound to DNA, Pt-GG and Pt-AG adducts after a 2 h 100 microM CDDP treatment. No significant difference is detected in the net formation of the Pt-GMP and G-Pt-G adducts. A slow Pt-AG adduct formation, with a maximum reached 10 h after CDDP composition, is found for both cell lines. In the 22 h period after the 2 h 100 microM CDDP treatment, a significant removal in GLC4 is measured for the Pt-GG, Pt-AG and the Pt-GMP adducts. For GLC4-CDDP a significant removal is detected in the total Pt bound to DNA, the Pt-AG and the Pt-GMP adducts. The removal of the total Pt bound to DNA in GLC4-CDDP cannot be explained by an adduct measured with the immunochemical method. In conclusion, no evidence is found that CDDP resistance is based upon the repair of the Pt-GG, Pt-AG, G-Pt-G and Pt-GMP adducts.

Carcinoma, Small Cell↗
PubMed1990

The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line.

The role of glutathione (GSH) in resistance to cisplatin (CDDP) was studied in a human small cell lung carcinoma cell line (GLC4) and a CDDP-resistant subline (GLC4-CDDP). In addition to studying the steady state of GSH, the kinetics of this defence system were also studied via the monitoring of the GSH status of the cells under continuous pressure of CDDP. GLC4-CDDP maintained its elevated GSH level whereas GLC4 (under pressure of CDDP) quickly synthesised GSH to about twice its initial level, corresponding with 80% of the GSH level of GLC4-CDDP. D,L-buthionine-S,R-sulphoximine (BSO) was used to analyse the role of GSH in resistance to CDDP. Pretreatment with BSO (48 h, 50 microM, GSH not detectable) increased the CDDP-induced cytotoxicity 2.8-fold in GLC4-CDDP and 1.7-fold in GLC4. In GLC4 no changes in the amount of platinum (Pt) bound to DNA could be observed after GSH depletion. Changes in formation of interstrand cross-links or the main Pt-containing intrastrand cross-link in digested DNA, the Pt-GG adduct, were also not observed. In GSH depleted GLC4-CDDP cells, an increase in the amount of Pt bound to DNA and in the Pt-GG adduct was observed. Pretreatment with BSO substantially reduced the repair of Pt bound to DNA in both cell lines. We conclude that an increased GSH level and GSH synthesis capacity were demonstrated in CDDP resistant cells. The observations after BSO treatment suggest two roles for GSH in CDDP resistance, namely that of a cytosolic elimination resulting in less DNA platination and a nuclear effect on the formation and repair of DNA platinum adducts.

Antimetabolites↗