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Biomedical subjects

N H Mulder

Publications and source records attributed to N H Mulder.

At least 145 records · Page 8Linked to original sources
PubMed1993

Topoisomerase II as a target of VM-26 and 4'-(9-acridinylamino)methanesulfon-m-aniside in atypical multidrug resistant human small cell lung carcinoma cells.

The Adriamycin-resistant small cell lung carcinoma cell line, GLC4/ADR, showed large differences in cross-resistance to drugs such as Adriamycin, etoposide (VP-16), teniposide (VM-26), 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA), and mitoxantrone, which stimulate the formation of topoisomerase (Topo) II-DNA complexes. GLC4/ADR cells demonstrated a reduced Topo II activity and no detectable levels of the P-glycoprotein compared to the parental GLC4 cells (S. De Jong et al., Cancer Res., 50: 304-309, 1990). In the present study, the resistance to VM-26 (59.5-fold) and to m-AMSA (4-fold) of GLC4/ADR after a 1-h incubation was further analyzed. Using the K(+)-sodium dodecyl sulfate precipitation assay, a reduction in VM-26- and m-AMSA-induced cleavable complex formation was found in GLC4/ADR cells compared to GLC4 cells that was related to the degree of resistance to each drug. Cellular accumulation of the VM-26 analogues VP-16 was 3- to 8-fold less and the accumulation of m-AMSA 1- to 2-fold less in GLC4/ADR cells than in the parental cells. Following the removal of VM-26, the cleavable complexes in GLC4/ADR cells disappeared at least 2-fold faster than in GLC4 cells, while the efflux of VP-16 was also enhanced in the resistant cells. On the contrary, no differences in cleavable complex disappearance or drug efflux between these cell lines were observed with m-AMSA. Efflux of both drugs, however, occurred at a much higher rate than cleavable complex disappearance. Using isolated nuclei, a reduction in cleavable complexes in GLC4/ADR was still observed with VM-26 as well as m-AMSA compared to GLC4. The resistant nuclei and nuclear extracts showed a 3-fold decrease in M(r) 170,000 Topo II by immunoblotting. No differences in cleavable complex formation were found between nuclear extracts of both cell lines, when the Topo II activities were equalized. These findings suggest that the cross-resistance to m-AMSA is due to a decreased amount of Topo II and decreased drug accumulation, while in addition to these mechanisms an increased rate of cleavable complex disappearance is involved in the cross-resistance to VM-26 of the GLC4/ADR cell line.

Amsacrine↗
PubMed1993

Effect of novobiocin on cisplatin cytotoxicity and DNA interstrand cross-link formation in a cisplatin-resistant, small-cell lung carcinoma cell line.

Studies were performed to determine whether novobiocin can be used to enhance cisplatin (CDDP) cytotoxicity in a human small-cell lung carcinoma cell line, GLC4/CDDP, resistant to CDDP. Continuous incubation with novobiocin enhanced the cytotoxicity of CDDP treatment 1.9-fold in the parental cell line GLC4, but had no effect on its cytotoxicity in the resistant cell line GLC4/CDDP. Short incubation with novobiocin enhanced the cytotoxicity of CDDP treatment in GLC4 and GLC4/CDDP by a factor of 4.1 and 2.8, respectively. Using the latter schedule, the amount of CDDP-induced DNA interstrand cross-links (DNA ISC) at 4 hr as well as at 24 hr after novobiocin and CDDP treatment was higher in GLC4 than in GLC4/CDDP. In this case, the amount of DNA ISC had increased 1.6-fold in GLC4 and 1.3-fold in GLC4/CDDP at 4 hr, and 2.7-fold and 1.4-fold, respectively, in these cell lines at 24 hr after treatment compared to CDDP treatment alone. Our results suggest an effect of novobiocin on the formation of DNA ISC. The decreased efficacy of novobiocin, an inhibitor of DNA topoisomerase (Topo) II catalytic activity, in GLC4/CDDP may be due to the increased Topo II activity previously found in the resistant cells. In the present study, we showed that increased Topo II activity was not due to changes in amounts of Topo II in nuclei or nuclear extracts of GLC4/CDDP. Further analysis of the chromatin, that includes Topo II, showed that the chromatin in nuclei of GLC4/CDDP was more sensitive to micrococcal nuclease digestion than GLC4. In addition, the amount of a 56-kDa protein was increased 2-fold in nuclei and nuclear matrices from GLC4/CDDP. The reduced efficacy of novobiocin to increase the CDDP cytotoxicity as well as the formation of DNA ISC in GLC4/CDDP compared to GLC4 may be due to changes in the chromatin structure of the resistant cells.

Carcinoma, Small Cell↗
PubMed1993

Local antitumour treatment in carcinoma patients with bispecific-monoclonal-antibody-redirected T cells.

In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24-48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24-48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest that the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48-72 h after treatment.

Abdominal Neoplasms↗
PubMed1993

HLA-Dr-expressing CD8bright cells are only temporarily present in the circulation during subcutaneous recombinant interleukin-2 therapy in renal cell carcinoma patients.

The effect of subcutaneous recombinant interleukin-2 (rIL-2) therapy on the "activation status" of peripheral blood lymphocytes (PBL) of 17 renal cell carcinoma patients was investigated in a longitudinal study. The expression of the activation markers HLA-Dr and CD25 on cytotoxic T cells, helper T cells, and natural killer (NK) cells, was analysed using two-colour flow cytometry of whole-blood samples. In addition, the ability of isolated PBL to proliferate in vitro in response to various stimuli was investigated. The absolute amounts of NK cells and HLA-DR-expressing NK cells increased continuously during the whole course of therapy. The absolute amounts of T cells and HLA-Dr-expressing T cells, however, showed an early increase only during the first 1 or 2 weeks of therapy, after which the absolute amounts of HLA-Dr-expressing T cells decreased. In particular, the absolute amount of HLA-Dr-expressing CD8bright+ T cells was significantly lowered in the second half of therapy. PBL collected on day 7 of therapy (post-cycle-1 PBL) showed, as compared to those collected prior to therapy (pretherapy PBL), a decreased proliferative response in vitro after stimulation with phytohaemagglutinin, concanavalin A, soluble CD3 mAb (WT32) or rIL-2. This decreased in vitro response of post-cycle-1 PBL was also reflected in a decrease in the percentage of CD8bright+ T cells expressing HLA-Dr in cultures with rIL-2 or CD3 mAb, in contrast to cultures of pretherapy PBL, which showed an increase of this percentage. We conclude that T cells are the predominantly stimulated subpopulation during the first 2 weeks of subcutaneous rIL-2 therapy. The significant decrease in the absolute amounts of HLA-Dr-expressing T cells in the peripheral blood during the second half of therapy may partly be explained by a decreased responsiveness to rIL-2, but a selective redistribution of HLA-Dr-expressing cells may also be involved.

Adult↗
PubMed1993

Phase I/II study of low-dose intravenous OKT3 and subcutaneous interleukin-2 in metastatic cancer.

In a phase I/II study the safety, immunostimulatory and antitumor effects of a combined OKT3/interleukin 2 (IL-2) treatment was studied in 15 cancer patients who failed IL-2 treatment. OKT3 was given as a 2-h intravenous infusion. Doses of 50, 100, 200 and 400 micrograms OKT3 were studied. Within 24 h, subcutaneous IL-2 was started 5 days/week for 4 weeks, at a dose of 9-18 x 10(6) U daily. Maximum tolerated dose was 400 micrograms OKT3 with neurotoxicity as dose-limiting toxicity. Toxicity of subcutaneous IL-2 was acceptable. At the maximum tolerated dose, 9 patients with renal cell carcinoma with measurable disease were treated in a phase II setting. 8 patients were evaluable for response. 4 patients had stable disease and 4 had progressive disease. An increase of activated lymphocyte subpopulations could not be found, although OKT3 was detectable on lymphocytes in vivo. Only if laboratory studies shed light on methods of improving immunostimulating effects of OKT3 will further clinical studies be warranted.

Adult↗
PubMed1993

Phase I-II study of the addition of alpha-2a interferon to 5-fluorouracil/leucovorin. Pharmacokinetic interaction of alpha-2a interferon and leucovorin.

5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.

Adult↗
PubMed1993

Zeniplatin in patients with advanced ovarian cancer, a phase II study with a third generation platinum complex.

25 patients with residual or recurrent ovarian cancer were treated with the new platinum complex zeniplatin (CL 286,558) and 23 patients were evaluable for response. Responses were achieved in 4 patients, 1 complete and 3 partial remissions (16%). 7 patients had stable disease and 12 patients had tumour progression. At a median follow-up of 12 months, the median progression-free survival in responding patients was 11 months and overall survival 81%. The median overall survival of progressive patients amounted to 9 months, indicating the advanced stage of disease in most patients. Renal function was monitored by isotope clearance studies. There was no significant change in effective renal plasma flow (ERPF) or glomerular filtration rate (GFR) in 10 patients who completed six cycles of treatment. 1 patient with a marginal creatinine clearance at baseline suffered from sudden and severe renal failure during the first cycle. Zeniplatin may be active in relapsing, platinum-pretreated patients, and has no direct effects on renal function as measured by isotope clearance. Despite these findings, occasional nephrotoxicity may occur in patients with compromised kidney function, even with prophylactic hydration, and thus limit the application of this new analogue.

Adult↗
PubMed1993

Antisense of oligonucleotides and the inhibition of oncogene expression.

Inhibition of oncogenes represents a new strategy that might lead to a better understanding of the different steps involved in tumorigenesis and also to the development of new therapeutic approaches. Attempts have been made to interfere with gene expression by in situ generation of mRNA from recombinant vectors (antisense RNA) or by the exogenous introduction of synthetic oligonucleotides (antisense oligonucleotides). Antisense oligonucleotides can inhibit the expression of specific genes by blocking the translation after hybridization with the target mRNAs--the antisense strategy. Antisense oligonucleotides can also be targeted to specific sequences of the DNA double helix. This causes inhibition of transcription--the antigene strategy. Regulatory sequences involved in controlling the transcription of oncogenes are used as targets for this type of 'antigene' oligonucleotide. Both strategies can be applied to control the oncogene expression of tumour cells in tissue culture, as exemplified in this review by myc antisense oligonucleotides. Recently the antisense strategy is moving into the area of clinical trials, aimed at curing chronic myelogenous leukaemia by ex vivo bone marrow purging. However, many difficulties have still to be overcome before the application of antisense oligonucleotides can be evaluated in the treatment of cancer.

Gene Expression Regulation, Neoplastic↗
PubMed1993

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

Adult↗
PubMed1993

A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer.

Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.

Administration, Oral↗
PubMed1993

A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.

A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1.

Adult↗
PubMed1993

Epithelial cell proliferation in the sigmoid colon of patients with adenomatous polyps increases during oral calcium supplementation.

To study the effect of oral supplemental calcium on colonic epithelial proliferation, 17 adenomatous polyp patients received 1.5 g Ca2+ as calcium carbonate daily during 12 weeks, while on a calcium constant diet, based on the patients' habitual diet. Seven subsequently continued calcium supplementation for 9 months without dietary restrictions. Epithelial proliferation rate in colonic biopsies, expressed as labelling index (%), was determined with 5-bromodeoxyuridine and immunohistochemistry. Biopsies were taken from the midsigmoid at time of polyp excision and at the end of the intervention period. Median labelling index increased from 6.1% before to 8.7% after 12 weeks calcium (n = 17, P < 0.02). This was due to increased labelling in the basal third of the crypts (11.9 vs 16%), whereas labelling in mid and luminal compartments was not affected. Labelling index remained increased after 1 year calcium supplementation at 8.8%. Crypt length was not affected by calcium. These results are in contrast to those of others, who have shown a decrease of rectal epithelial proliferation during similar doses of calcium. Therefore, the effect of nutritional intervention on colonic epithelial proliferation should be studied in biopsies taken not only from the rectum, but also from more proximal parts of the colon. Caution with respect to large scale intervention studies with calcium in high risk groups is mandatory.

Administration, Oral↗
PubMed1993

A phase I study of lobaplatin (D-19466) administered by 72 h continuous infusion.

A phase I trial with continuous intravenous infusion of lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) for 72 h was performed to determine the maximum tolerated dose (MTD). Each patient received a single dose level, the total dose of lobaplatin ranged from 30 to 60 mg/m2/72 h every 4 weeks. Eleven patients enroled in this study and received a total of 30 courses of lobaplatin (median 2; range 1-6). Thrombocytopenia was the dose-limiting toxicity, it reached WHO grade III in three out of six patients at 45 mg/m2/72 h, and WHO grade IV in two out of two patients at 60 mg/m2/72 h. Leucocytopenia was mild, as was nausea and vomiting. Phlebitis at the infusion site was found in three patients. During this trial there were no signs of renal, neuro- or ototoxicity. One patient with ovarian cancer, pretreated with three different platinum complexes, achieved a partial response now lasting for longer than 6 months. In conclusion, thrombocytopenia is the dose-limiting toxicity of lobaplatin administered by 72 h continuous infusion. The recommended phase II dose for this regimen is 45 mg/m2/72 h every 4 weeks.

Adult↗
PubMed1993

Effects of oral calcium supplementation on intestinal bile acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon.

Calcium has been proposed to prevent colon cancer in subjects at risk for this tumour. This effect is supposed to be due at least in part to binding the bile acids to calcium, making them insoluble and harmless. To evaluate the effects of oral calcium supplementation on intestinal bile acids, 19 patients with adenomatous colonic polyps were supplemented with 35.5 mmol Ca2+ daily for 12 weeks. Duodenal bile, 24-h feces and 24-h urine were collected before and at the end of the 12-week period. In duodenal bile proportional concentration of cholic acid increased (38 +/- 4 vs. 51 +/- 3%, P < 0.001), whereas that of chenodeoxycholic acid decreased (35 +/- 3 vs. 25 +/- 2%, P < 0.01). Total fecal bile acid excretion increased (950 +/- 126 vs. 1218 +/- 137 mumol 24 h-1, P < 0.01), with proportional concentrations of the main primary and secondary bile acids remaining the same. Cytolytic activity of fecal water, measured by the degree of lysis of erythrocytes by the water, decreased (45 +/- 8 vs. 30 +/- 7%, P < 0.05). Total excretion of calcium increased as expected from the supplementary dose. It is concluded that calcium supplementation markedly affects intestinal bile acids and lytic activity of fecal water and that, in view of similar results during 1-week calcium supplementation in young healthy subjects, these effects remain constant over at least 3 months and occur both in healthy persons and in patients at increased risk for colon cancer.

Bile Acids and Salts↗
PubMed1993

Recent developments in diagnosis and treatment of metastatic carcinoid tumours.

In carcinoid patients a tumour of enterochromaffin cell origin is present, which dependent on the site of origin can result in increased serotonin production. Metastasized carcinoids are often diagnosed by measuring 5-hydroxyindoleacetic acid excretion in the urine. This excretion, however, can be influenced by food intake. On the other hand, serotonin measured in blood platelets is unaffected by food intake and, in addition, is found to be more sensitive. Therapy of metastasized carcinoids is directed at tumour reduction or only reduction of symptoms. Tumour reduction can be achieved surgically or by embolization. Combination chemotherapy has a maximum response percentage of about 33%. Over the last few years, both octreotide and interferon alpha have been used in these patients. They rarely result in a reduction of the tumour size (10-20%). Symptom reduction is achievable in most patients with these agents, however. Recently, increasing knowledge obtained concerning the various serotonin receptors and their antagonists is now being used in the treatment of patients with a metastasized carcinoid. In the future it is expected that the different modalities will be combined increasingly.

Antineoplastic Combined Chemotherapy Protocols↗