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N H Mulder

Publications and source records attributed to N H Mulder.

At least 19 recordsLinked to original sources
PubMed1995

Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients.

Initial studies have shown that recombinant human interleukin-6 (rhIL-6) induces anemia. Until now, the pathophysiologic mechanism of this induced anemia has been unknown. To unravel the underlying mechanism, we examined 15 cancer patients receiving rhIL-6 as an antitumor immunotherapy in a phase II study. rhIL-6 was administered subcutaneously at 150 micrograms once daily for 6 consecutive weeks. Various hematologic and biochemical parameters were measured weekly during rhIL-6 treatment and 4 weeks after rhIL-6 discontinuation. To determine plasma volume and red blood cell (RBC) volume, radioisotope dilution assays with labeled autologous RBCs and with human serum albumin were performed before rhIL-6 administration and on day 8 of rhIL-6 therapy. Hemoglobin levels decreased (mean change +/- SE) 7% +/- 1.5% within 3 days after the start of rhIL-6 therapy (P < .0001) and 19% +/- 2% at week 4. Levels had normalized at follow-up. The plasma volume increased 18% +/- 5% during the first week of rhIL-6 administration (P < .003), whereas RBC volume remained unaffected. The mean RBC corpuscular volume remained unchanged for 2 weeks and then began to decrease slowly, reaching its nadir at week 6 (5% +/- 1%; P < .01). Serum iron levels decreased 65% +/- 12% at week 4 (P < .002) and then returned to initial baseline values. Erythropoietin levels increased rapidly up to 68% at week 3 (P < .0001) and had normalized 4 weeks after rhIL-6 therapy. Levels of serum albumin, prealbumin, and transferrin decreased (P < .0001, P < .003, and P < .0001, respectively), whereas levels of serum amyloid A (P < .003), C-reactive protein, haptoglobin, and alpha-1-antitrypsin (P < .0001) increased during rhIL-6 treatment. All levels returned to pretreatment values after discontinuation of rhIL-6. No alterations in reticulocyte counts, serum lactic dehydrogenase levels, and bilirubin levels were observed. A 6-week regimen of subcutaneous rhIL-6 results in a rapid dilution anemia, caused by an acute and significant increase in plasma volume and followed by hypoferremia. This anemia is reversible after the cessation of rhIL-6 treatment.

Acute-Phase Proteins↗
PubMed1995

Resistance-associated factors in human small-cell lung-carcinoma GLC4 sub-lines with increasing adriamycin resistance.

Previous studies have shown that the in vitro-selected adriamycin-resistant human small-cell lung-carcinoma cell line GLC4-ADR150 displays multidrug resistance as the result of 3-fold decreased DNA-topoisomerase II (topo II) activity and a 6-fold reduction in adriamycin accumulation. Not the MDR1 gene, but the MRP gene, was over-expressed in this cell line. The aim of our study was to establish which of these drug-resistance-associated factors are already involved in drug resistance occurring at early steps of selection with adriamycin. To address this question, changes in expression of topo II alpha/topo II beta, MRP and drug accumulation were measured along with adriamycin resistance (from 2- to 10- to 150-fold) and in a partial revertant cell line (10-fold resistant). Topo II alpha and II beta mRNA and protein levels were decreased in the resistant sub-lines, except in the 10-fold-resistant cell line. Cellular daunorubicin accumulation was decreased 1.2- to 5-fold with increasing resistance. MRP mRNA was over-expressed in all resistant sub-lines, with a marked increase in the 10-fold-resistant cells (level of expression as high as in the GLC4-ADR150 cells). Expression of an ATP-binding 190-kDa membrane protein and Western-blot analysis with anti-MRP anti-serum ASPKE, was in accordance with the expression of MRP mRNA in all cell lines. Expression of MRP mRNA and protein, however, was not proportional with the decrease in drug accumulation in all resistant sub-lines. This study also shows that drug accumulation, topo II and MRP expression were all changed at the earliest stage of resistance development of GLC4 cells upon adriamycin selection.

ATP-Binding Cassette Transporters↗
PubMed1995

Randomized, double-blinded, placebo-controlled intervention study with supplemental calcium in families with hereditary nonpolyposis colorectal cancer.

BACKGROUND: A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. PURPOSE: We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. METHODS: Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO3) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. RESULTS: Statistically significant reductions, comparing before with after intervention, in rectal whole-crypt LI after receiving either calcium supplements (from 10.9% +/- 5.2% [mean +/- SD] to 6.2% +/- 1.5%; P < .02) or placebo (from 11.7% +/- 4.7% to 8.2% +/- 3.1%; P < .05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% +/- 41% to 32% +/- 30%; P < .05), whereas in the placebo group, it did not change (from 42% +/- 41% to 36% +/- 27%; P > .10). CONCLUSIONS: Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. IMPLICATION: These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium.

Adolescent↗
PubMed1995

5-Fluorouracil/leucovorin/interferon alpha-2a in patients with advanced colorectal cancer. Effects of maintenance therapy on remission duration.

BACKGROUND: A Phase II study of combination treatment with 5-fluorouracil (5-FU), leucovorin (LV), and interferon alpha-2a (IFN) in patients with previously untreated metastatic colorectal cancer was previously reported by the authors. Therapy was on an outpatient basis and consisted of LV 60 mg orally every 8 hours days 1-3, IFN 18 x 10(6) IU subcutaneously days 1-3, and bolus 5-FU 750 mg/m2 intravenously days 2-3. Treatment was repeated every 14 days, until a maximum of 8 courses was administered. A response rate of 54% [95% confidence interval (CI), 34-72%] was observed. However, remission duration after cessation of therapy was short, with a median duration of 5 months (range, 2 to 13+ months). METHODS: Subsequent to the above study, patients on this induction treatment who achieved remission received maintenance therapy: the above described 3-day regimen every 6 weeks until progression, for a maximum of 2 years. RESULTS: Fifty-three patients were enrolled in the induction regimen and 18 out of 29 patients who achieved remission received maintenance treatment. In 50 assessable patients 3 complete recoveries and 26 partial recoveries were observed for a response rate of 58% (CI, 43-72%). Median remission duration of patients receiving maintenance therapy was 9.4 months (CI, 8.4-10.3 months) compared with 4.7 months (CI, 3.2-6.2 months) for patients without maintenance therapy. Median overall survival of all patients was 16.6 months. Toxicity of maintenance therapy was confined to WHO grade 2. CONCLUSIONS: The high response rate of this 5-FU/LV/IFN regimen holds true in a larger group of patients. The group that received maintenance treatment had a remission duration of just over 9 months, the maintenance regimen added little toxicity.

Adult↗
PubMed1995

Cell biological markers of drug resistance in ovarian carcinoma.

The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclophosphamide/melphalan), natural drugs (doxorubicin), and "new drugs" (taxol and taxotere). Both platinum and classical alkylating agents mediate their cytotoxicity by the formation of drug-DNA adducts, resulting in DNA damage. Therefore, drug resistance mechanisms are (in part) comparable. In ovarian carcinoma cell lines increased repair of DNA damage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs. Studies on the role of DNA repair mechanisms and glutathione in human ovarian carcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione. Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell by increased expression of membrane glycoproteins acting as a drug efflux pump, such as P-glycoprotein. Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topisomerase (Topo) II. Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presumed other mechanisms such as alterations in tubulin structure, the cellular "target" of taxol, and changes in polymerization of tubulin are still largely unresolved. Several ways to modulate the reviewed resistance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance. The relevance of the identification of most of these factors in ovarian carcinoma patients however remains to be established.

Alkylating Agents↗
PubMed1995

The role of methoxymorpholino anthracycline and cyanomorpholino anthracycline in a sensitive small-cell lung-cancer cell line and its multidrug-resistant but P-glycoprotein-negative and cisplatin-resistant counterparts.

The cytotoxic action of two morpholino anthracyclines, methoxymorpholino anthracycline (MRA-MT, FCE 23,762) and cyanomorpholino anthracycline (MRA-CN), was compared with the cytotoxicity of doxorubicin (DOX), the topoisomerase II inhibitor etoposide (VP-16), the topoisomerase I inhibitor camptothecin, methotrexate, and cisplatin in GLC4, a human small-cell lung-cancer cell line, in GLC4-Adr, its P-glycoprotein (Pgp)-negative, multidrug-resistant (MDR; 100-fold DOX-resistant) subline with overexpression of the MDR-associated protein (MRP) and a lowered topoisomerase II activity, and in GLC4-CDDP, its cisplatin-resistant subline. GLC4-Adr was about 2-fold cross-resistant for the morpholino anthracyclines and GLC4-CDDP was, relative to GLC4, more resistant for the morpholino anthracyclines than for DOX. Overall, MRA-CN was about 2.5-fold more cytotoxic than MRA-MT. The cytotoxicity profile of the morpholino anthracyclines in these cell lines mimicked that of camptothecin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Phase II study of intraperitoneal cisplatin plus systemic etoposide as second-line treatment in patients with small volume residual ovarian cancer.

The efficacy and toxicity of intraperitoneal (i.p.) cisplatin plus systemic etoposide were studied in 36 patients with small (< 2 cm) residual i.p. ovarian cancer after achieving a partial response to platinum-based, first-line chemotherapy. Treatment comprised 90 mg/m2 i.p. cisplatin with intravenous (i.v.) sodium thiosulphate (day 1) and 600-800 mg/m2 i.v. etoposide (days 1 and 2), every 4 weeks for four to six cycles. 7 patients achieved a pathological complete response (pCR), one a pathological partial response and 16 were clinically stable without evidence of disease. After a median follow-up of 13 months, the median progression-free survival (PFS) was 11 months (95% confidence interval 7-16 months). The actuarial PFS at 24 months is 22% (95% confidence interval 8-36%). Three of six relapses after achieving a pCR (50%) were sited i.p., and 9 of 14 other patients with disease progression (64%) had an i.p. relapse, indicating insufficient local efficacy. There was no renal toxicity, but grade 3-4 leucopenia occurred in 63% and grade 3-4 thrombocytopenia in 8% of cycles, while nausea, vomiting and complete alopecia were common. Although side-effects were acceptable, the efficacy of treatment with i.p. cisplatin plus i.v. etoposide is limited.

Administration, Topical↗
PubMed1995

Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines.

Cisplatin (CDDP) resistance mechanisms were studied in a model of three germ cell tumour and three colon carcinoma cell lines representing intrinsically CDDP-sensitive and -resistant tumours respectively. The CDDP sensitivity of the cell lines mimicked the clinical situation. The glutathione levels of the cell lines correlated with CDDP concentrations inhibiting cell survival by 50% (IC50); total cellular sulphydryl content (TSH) was unexpectedly inversely correlated with IC50. IC50 correlated neither with glutathione S-transferase (GST) nor with GST pi expression, topoisomerase I or II activity. Immediately after 4 h incubation with CDDP, platinum (Pt) accumulation and Pt bound to DNA were not correlated, but after another 24 h drug-free culture, Pt binding to DNA in germ cell tumour but not in colon carcinoma cell lines correlated with IC50. With the exception of in vitro sensitivity and TSH, none of the parameters studied discriminated between the two groups of cell lines. Correction of CDDP sensitivity parameters for phenotypical differences did not influence statistical correlations. Analysis of variance revealed a correlation between IC50 and the combination of glutathione, GST activity and Pt bound to DNA. But at other CDDP cytotoxicity levels sensitivity was also correlated with Pt accumulation, topoisomerase II activity and TSH in various combinations. This model of intrinsic CDDP resistance showed that multiple parameters ought to be studied to explain CDDP resistance, but did not elucidate the cause of the unique sensitivity of germ cell carcinoma, although the unexpected values of TSH deserve further attention.

Adenocarcinoma↗
PubMed1995

Decrease in pulmonary function during bleomycin-containing combination chemotherapy for testicular cancer: not only a bleomycin effect.

This study was performed to determine the changes in pulmonary function in patients randomised to receive treatment with four cycles of bleomycin, etoposide and cisplatin (BEP) (27 patients) or with four cycles of etoposide and cisplatin (EP) (27 patients) for disseminated non-seminomatous testicular cancer. This enabled us to establish whether effects other than those due to bleomycin determined the detrimental effects of BEP on lung function assessments. Slow inspiratory vital capacity (VC), the transfer factor of the lungs for carbon monoxide (TLCO), the diffusing capacity of the alveolo-capillary membrane (Dm), the pulmonary capillary blood volume (Vc) and the transfer factor of the lungs for carbon monoxide per unit alveolar volume (KCO) were determined before and at 3 week intervals during chemotherapy. Both groups, similar in terms of factors that may influence pulmonary function, showed during therapy a significant decrease in TLCO compared with the pretreatment value. Only at the end of the therapy was a significant difference in TLCO between both groups observed. Dm diminished also significantly in both groups during treatment, but differences between both groups were not seen. VC and Vc decreased in patients receiving BEP but remained constant during treatment with EP. It can be concluded that the Dm, KCO, and the widely used TLCO are not suitable parameters to monitor specifically pulmonary toxicity induced by bleomycin as part of a multidrug regimen. However, VC and Vc appear to be proper lung function assessments which reflect specifically alterations induced by bleomycin.

Adolescent↗
PubMed1995

Immunomodulatory effects of intravenous BIS-1 F(ab')2 administration in renal cell cancer patients.

We report the immunomodulatory effects of an intravenous treatment with F(ab')2 fragments of the bispecific monoclonal antibody BIS-1 during subcutaneous recombinant interleukin 2 (rIL-2) therapy of renal cell cancer (RCC) patients. BIS-1 is directed against both the CD3 antigen on T cells and the EGP-2 molecule on carcinoma cells and some normal epithelia. The amount of BIS-1 F(ab')2 bound to peripheral blood lymphocytes (PBLs) increased dose-dependently. This occupation degree was highest at the end of the 2 h infusion and rapidly decreased subsequently. During the first hour of BIS-1 F(ab')2 infusion the number of PBLs decreased slowly. This was followed by an increase in serum tumour necrosis factor alpha (TNF-alpha) concentrations and a rapid decrease in the numbers of peripheral blood lymphocytes, monocytes and eosinophils. In our view, the most likely explanation for the observed decrease in occupation degree of BIS-1 F(ab')2 and the rise in TNF-alpha levels is based on the assumption that BIS-1-carrying T cells leave the circulation. The CD3 antigens on these extravasated T cells become cross-linked by EGP-2 antigens, inducing TNF-alpha secretion. This results in an enhanced decrease in the numbers of PBLs, monocytes and eosinophils. These preliminary results suggest that BIS-1 F(ab')2 treatment during IL-2 therapy may induce local T-cell activation.

Adjuvants, Immunologic↗
PubMed1995

Continuous carboplatin infusion during 6 weeks' radiotherapy in locally inoperable non-small-cell lung cancer: a phase I and pharmacokinetic study.

A phase I study was performed in 21 patients with previously untreated, locally inoperable, non-small-cell lung cancer (NSCLC) with ambulatory continuous carboplatin infusion together with continuous thoracic irradiation over 6 weeks. A dose range for carboplatin of 15 mg m-2 day-1 during the last 21 days (first level), during the last 31 days (second level), or during 6 weeks of the radiation period (third level) and thereafter 20 or 25 mg m-2 day-1 during 6 weeks of radiation (fourth and fifth level) was used. The total radiation dose was 60 Gy given as 2 Gy day-1 for 5 days week-1. The first three patients received radiotherapy without carboplatin. WHO grade III/IV leucopenia and thrombocytopenia occurred in the last two dose levels in two out of six and one out of six patients with 20 mg m-2 day-1 respectively, and in all three patients with 25 mg m-2 day-1 (dose-limiting toxicity). One local infection around the port and a subclavian vein thrombosis occurred. Radiation toxicity of the lung and oesophagus did not seem to be influenced by carboplatin treatment. Out of 21 patients one had a complete response (CR), ten partial response (PR), six stable disease (SD) and four progressive disease (PD). Total (TPt) and ultrafilterable plasma platinum (UPt) were measured in the last three dose levels with atomic absorption spectrophotometry with Zeeman correction. The mean (s.d.) level for TPt for 6 weeks at 15, 20 and 25 mg m-2 day-1 was 0.76 (0.15), 0.78 (0.19) and 0.90 (0.22) mg l-1 for UPt 0.10 (0.03), 0.12 (0.02) and 0.20 (0.03) mg l-1 respectively. TPt concentration levelled off after 3 weeks. The mean (s.d.) CLTB for UPt was 281 +/- 21 ml min-1 and correlated with glomerular filtration rate (r = 0.61, P = 0.03). As estimated with the sigmoid Emax model defined by the Hill equation the percentage reduction in platelets correlated with the area under the curve for UPt (r = 0.77). The maximum tolerable dose of carboplatin with concomitant continuous 60 Gy radiotherapy is 25 mg m-2 day-1; the recommended dose for phase II or III studies is 20 mg m-2 day-1 day for 6 weeks.

Adult↗
PubMed1995

In vitro and in vivo studies on the action of BW502U83, an arylmethylaminopropanediol.

BW502U83, an arylmethylaminopropanediol (AMAP), showed to be partially cross-resistant in a P-glycoprotein-positive and in a P-glycoprotein-negative, doxorubicin-resistant cell line, while no cross-resistance was noticed in a cisplatin-resistant cell line. Interstrand cross-links were not observed, but BW502U83 induced extensive DNA strand breaks. In a feasibility study the effect of intra-arterially BW502U83 was tested. One patient with a hepatocellular carcinoma showed partial remission and signs of a tumor lysis syndrome, another patient with a hepatocellular carcinoma improved clinically. A patient with soft tissue sarcoma had stable disease. Transient increase in SGOT, SGPT and LDH were observed, but no systemic side effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer.

PURPOSE: To evaluate the safety, tolerability, and efficacy of varying doses of recombinant human interleukin-6 (rhIL-6) after chemotherapy. PATIENTS AND METHODS: In this phase I/II study, 19 breast (stage III to IV) or non-small-cell lung cancer (NSCLC) patients received mitoxantrone (10 mg/m2) and thiotepa (40 mg/m2) every 3 weeks, followed by rhIL-6 subcutaneously (days 5 to 15) at six dose levels: 0.5, 1.0, 2.5, 5.0, 10.0, and 20.0 micrograms/kg/d body weight/d (micrograms/kg/d). rhIL-6 was increased to the next level in the individual patient in case of incomplete bone marrow recovery (leukocyte count < 3 x 10(9)/L and/or platelet count < 100 x 10(9)/L at day 22) and/or platelet nadir less than 25 x 10(9)/L in two consecutive cycles. RESULTS: Flu-like symptoms were observed in most of the patients. Nausea and vomiting were reported in seven of 48 and 19 of 48 cycles, respectively. Dose-limiting toxicity at 20.0 micrograms/kg/d of rhIL-6 consisted of World Health Organization (WHO) grade 3 to 4 flu-like symptoms, nausea, and vomiting. Platelet recovery was faster in cycle 1 at 10.0 and 20.0 micrograms/kg/d of rhIL-6 than at lower dose levels (P < .05); thrombocytopenia grade 4 was observed at most levels. However, only two patients needed platelet transfusions (1.0 and 2.5 micrograms/kg/d rhIL-6). rhIL-6 effects on leukocytes were not dose-related, with a trend for the neutrophil nadir to increase with rhIL-6 up to 10 micrograms/kg/d. rhIL-6 dose escalation did not affect hematologic parameters and chemotherapy cycle duration. Hemoglobin (P < .001) and cholesterol (P < .05) levels decreased, while acute-phase proteins increased. CONCLUSION: rhIL-6 following chemotherapy is tolerable up to 10 micrograms/kg/d; flu-like symptoms and nausea were dose-limiting at 20 micrograms/kg/d. Platelet nadir did not differ for the various rhIL-6 doses. However, a faster platelet recovery was observed at 10.0 and 20.0 micrograms/kg/d of rhIL-6.

Adult↗