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Biomedical subjects

N H Mulder

Publications and source records attributed to N H Mulder.

At least 235 records · Page 13Linked to original sources
PubMed1988

Characterization of a human small cell lung carcinoma cell line with acquired resistance to cis-diamminedichloroplatinum(II) in vitro.

A 6.4-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human small cell lung carcinoma cell line (GLC4-CDDP) was developed to study acquired CDDP resistance in vitro. Compared to the sensitive cell line (GLC4), the GLC4-CDDP showed an increase in doubling time and a decrease in cloning efficiency, cellular size, double minutes per cell, cellular protein, and nuclear protein content. While a complete cross-resistance for tetraplatin and a partial cross-resistance for doxorubicin, melphalan, cadmium chloride, carboplatin, and cis-dichloro-trans-dihydroxo-cis-bis(isoprolylamine)platinum (IV) (resistance factor, respectively,4.0,5.8,2.1,1.5,2.9) was found, no cross-resistance for vincristine was found. In the GLC4-CDDP line in comparison to the GLC4 line, glutathione and total amount of sulfhydryl compounds was significantly increased, while glutathione S-transferase and glutathione reductase was the same. The platinum content in cells and nuclei was lower in the resistant line, but after correction for cellular protein or volume no difference was found. The amount of platinum bound to DNA was significantly lower in the GLC4-CDDP line. After a 1-h incubation with CDDP, the amount of Pt-GG adducts was the same and the amount of interstrand cross-links was reduced in the GLC4-CDDP line as compared to GLC4. In conclusion, in the GLC4-CDDP line the phenotype and genotype are changed and various mechanisms, such as decreased Pt-DNA binding, elevated glutathione, and reduced interstrand cross-links, play a role in the development of the CDDP resistance.

Amino Acids↗
PubMed1988

Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up.

Three classic-type, small cell lung cancer cell lines (GLC-14, GLC-16, and GLC-19) have been established from one patient during longitudinal follow-up. During this period the tumor changed from sensitive to completely resistant to (chemo)therapy. A phenotypical and functional characterization of the different cell lines is given in combination with the matching clinical data. (a) The cell lines have been compared with the biopsies from which they were derived. There was a good match between the morphological, biochemical, and immunohistological findings in the cell lines as compared to those obtained in the biopsies. When the biopsy and cell line (GLC-14) obtained before the start of therapy were compared to the biopsies and cell lines (GLC-16 and GLC-19) acquired after the first and second reinduction therapy, respectively, no major changes could be observed. The only clear alteration was the loss of a neuroendocrine antigen (defined by monoclonal antibody MOC-51) in the posttherapy specimens. (b) The doxorubicin, melphalan, and etoposide sensitivity in vitro reflected the clinically observed development of resistance to treatment. The cell line (GLC-14) established before the start of therapy was more sensitive than the lines (GLC-16 and GLC-19) obtained after treatment. It is concluded that the cell lines described in this paper represent a well-characterized in vitro model in which the development of drug resistance in small cell lung cancer can be studied.

Antigens, Differentiation↗
PubMed1988

Results of adjuvant surgery in patients with stage III and IV nonseminomatous testicular tumors after cisplatin-vinblastine-bleomycin chemotherapy.

From January 1978 to April 1983, 53 patients were treated with cisplatin-vinblastine-bleomycin chemotherapy because of advanced nonseminomatous testicular tumor (NSTT). After the chemotherapy, the serum tumor markers were back to normal in 41 patients, of whom 35 were eligible for surgical removal of the residual tumor. In four patients, vital tumor tissue was found in the residual tumor. Salvage chemotherapy resulted in complete remission. Residual mature teratoma was encountered after the chemotherapy in 15 of the 25 patients with a teratomatous component and in one of the ten patients without a teratomatous component in the primary tumor. On completion of the study, 38 of the 53 patients (72%) are still alive, with a median follow-up of 65 months. Subdivided by tumor volume, survival is found to amount to 92% for small-volume disease, 67% for large-volume disease, and 64% for very-large-volume disease. Six patients (11%) developed a recurrence in the course of the follow-up. Exploratory laparotomy after remission induction chemotherapy is necessary in all patients with a teratomatous component in the primary testicular tumor who have become tumor marker negative, irrespective of the roentgenographic findings of the retroperitoneum. Patients without a teratomatous component in the primary tumor should have exploratory laparotomy only in case of roentgenographic evidence of retroperitoneal residual tumor. A thoracotomy is needed only in the presence of roentgenographic evidence of pulmonary residual lesions.

Adolescent↗
PubMed1988

Renal dysfunction following high-dose carboplatin treatment.

A case history is reported or renal failure during and after treatment with carboplatin for 3 days, total dose 750 mg/m2, in a conditioning regimen prior to autologous bone marrow transplantation. Pretreatment renal function was compromised after nephrectomy and chemotherapy with cisplatin. A decrease in glomerular filtration rate concurred with a decrease in excretion of platinum in the urine and an increase in urinary beta 2 microglobulin. Treatment with high-dose carboplatin in patients with impaired renal function and previous treatment with cisplatin may lead to further loss of renal function.

Adult↗
PubMed1988

Mechanisms of cellular resistance to cisplatin.

Treatment of cancer patients often fails because of the resistance in the tumor to chemotherapeutic drugs. A better understanding of mechanisms which are active in resistant cells might lead to measures to circumvent the resistance. This review deals with the mechanisms of action of cisplatin (CDDP) and the various causes for CDDP resistance in the tumor cells. Also, possibilities to circumvent CDDP resistance in vitro and in vivo are presented.

Biological Transport↗
PubMed1988

Graft versus host disease after transfusions of non-irradiated blood cells in patients having received autologous bone marrow. A report of 4 cases following ablative chemotherapy for solid tumors.

In four patients with solid tumors (three small cell lung cancers, one germ cell cancer) high dose chemotherapy with autologous bone marrow infusion was given. Graft versus host disease (GVHD) was the cause of death in one patient and at autopsy signs of GVHD were found in the other three patients. In these four patients GVHD was caused by blood cell transfusion. Patients treated with aggressive chemotherapy for solid tumors are at risk for the development of GVHD after allogeneic blood cell transfusions and preventive measures are definitely needed.

Adult↗
PubMed1988

Chemotherapy with maximally tolerable doses of VP 16-213 and cyclophosphamide followed by autologous bone marrow transplantation for the treatment of relapsed or refractory germ cell tumors.

Eleven patients with advanced nonseminomatous germ cell tumors (NSGCT), who relapsed after or were refractory to standard dose cisplatin-based remission induction chemotherapy, were treated in a phase II clinical trial with VP 16-213 2500 mg/m2 and cyclophosphamide 7 g/m2. Both drugs were given in maximally tolerable doses regarding extramedullary toxicity. Urothelial damage due to cyclophosphamide was prevented by the administration of mesnum. Autologous bone marrow was infused on day 7 to prevent long lasting medullary toxicity. Because of the disappointing results in the first three patients, a second treatment step was added. The next eight patients were treated with 2500 mg/m2 VP 16-213 divided and given on days 1-2-3 and after full bone marrow recovery with total doses of VP 16-213 2000 mg/m2 plus cyclophosphamide 7 g/m2 divided and given on days 29-30-31, followed by autologous bone marrow transplantation (ABMT) on day 35. Toxicity to high-dose VP 16-213 plus cyclophosphamide followed by ABMT consisted of mucositis, nausea, vomiting and diarrhea. No cardiac toxicity or hemorrhagic cystitis occurred. The mean duration of leukopenia and thrombopenia was 14 and 13 days respectively. The additional, preceding treatment with VP 16-213 as a single agent caused mucositis, and leukopenia and thrombopenia for a mean number of 9 and 6 days respectively. Seven responses were obtained: two complete responses of 46 and 66+ weeks respectively and five partial responses with a median response duration of 12 weeks. The median survival time was 40 weeks. This regimen of one or two courses with maximally tolerable doses of VP 16-213 plus cyclophosphamide and ABMT is not sufficient to salvage a substantial number of patients with relapsing or refractory NSGCT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Clinical and endocrine effects of cyproterone acetate in postmenopausal patients with advanced breast cancer.

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.

Aged↗
PubMed1987

Influence of docosahexaenoic acid in vitro on intracellular adriamycin concentration in lymphocytes and human adriamycin-sensitive and -resistant small-cell lung cancer cell lines, and on cytotoxicity in the tumor cell lines.

An increase in the therapeutic effects of cancer chemotherapeutic agents and circumvention of drug resistance in cancer cells might result from an increase in the intracellular drug level. Alteration of the lipid domain of the cell membrane can result in a higher intracellular drug level. This alteration was achieved in human lymphocytes and in human adriamycin (ADR)-sensitive and -resistant small-cell lung carcinoma cells in vitro by incubation with docosahexaenoic acid (22:6). Incorporation of the fatty acid in cellular phospholipids was measured by gas chromatographic analysis. A significant increase of 22:6 could be reached without loss of viability in all 3 cell types. Incorporation was demonstrated notably in the phosphatidyl choline, phosphatidyl ethanolamine and phosphatidylserine, and was most pronounced in the phosphatidyl choline of the ADR-resistant line. After a 1-hr incubation with ADR, a 10-30% increase in intracellular adriamycin concentration was found in all 3 cell types previously incubated for 4 days with 22:6. After 1 hr incubation with ADR there was no increase in cytotoxicity in the sensitive cell line when measured by soft agar clonogenic assay and a partial reversal (52 to 14) of resistance factor (ratio of drug doses to produce 50% growth inhibition) in the resistant cell line. Increasing the time of ADR exposure from 1 to 4 hr further reduced the resistance factor to 8.6.

Biological Transport↗
PubMed1987

The protective potential of the combination of verapamil and cimetidine on cisplatin-induced nephrotoxicity in man.

Nine patients (Group A) with histologically proven, nonseminomatous testicular cancer were treated with cisplatin (CDDP) according to the Einhorn regimen. Renal function studies including the measurement of the effective renal plasma flow (ERPF) and the glomerular filtration rate (GFR) were performed prior to the chemotherapy and then after treatment on days 10 and 21 of the first course. In order to prevent CDDP-induced nephrotoxicity, verapamil (a calcium entry blocker) and cimetidine were given along with CDDP. The results were compared with others from another group of nine patients (Group B) treated with CDDP, but without verapamil and cimetidine. In Group A there was much less of a decrease in ERPF as compared to Group B on day 21. In addition, the decrease in GFR on days 10 and 21 was totally prevented in the verapamil- and cimetidine-treated group.

Adult↗
PubMed1987

Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line.

In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured without Adr for 3 months, has a decreased but stable resistance factor of 8. One of the assumed mechanisms of Adr is that the effect is mediated through the formation of free radicals. Therefore free radical scavenging might play a role in these Adr resistant cell lines. Adr, H2O2, and X-ray induced cytotoxicity were evaluated. Glutathione (GSH) levels and activities of associated enzymes were determined as well as Adr, H2O2, and X-ray induced DNA breaks and repair. GSH level was decreased in GLC4-Adr1, but restored to the normal level in GLC4-Adr2. Superoxide dismutase, catalase, glutathione-peroxidase, and glutathione S-transferase were not elevated in the resistant sublines. Adr induced a decreased amount of DNA breaks in GLC4-Adr1 compared to GLC4. For X-ray and H2O2 a comparable amount of DNA damage was found. GLC4-Adr1 was able to repair DNA breaks induced by Adr, X-ray, and H2O2 better than GLC4. In conclusion, no increased enzyme capacity for detoxification of free radicals could be detected in the cytosol of the resistant cells. The resistance against free radicals in the GLC4-Adr1 line may at least in part be a result of increased DNA repair.

Carcinoma, Small Cell↗
PubMed1987

Multifactorial drug resistance in an adriamycin-resistant human small cell lung carcinoma cell line.

In a human small cell lung carcinoma cell line, GLC4, Adriamycin (ADR) resistance was induced. In the resistant cell line, GLC4/ADR, a 45% decreased intracellular ADR level was found compared to GLC4, but this could not fully explain the resistance. Evaluation of DNA damage in both cell lines after incubation with ADR by alkaline and neutral elution revealed single-strand breaks, DNA-protein cross-links, and double-strand breaks (DSB). At all incubation concentrations there was a decreased amount of all types of DNA damage in GLC4/ADR. The number of DSB was decreased also when corrected for the decreased intracellular concentration. This can at least partly be explained by the decreased stability of ADR induced DSB. After removal of ADR, 80% of DSB was repaired in 1 h in GLC4/ADR against no repair in GLC4. X-ray induced DSBs were also repaired faster: in GLC4/ADR t1/2 = 10 min and in GLC4 t1/2 = 23 min. Ratios for single strand breaks/DSBs and single strand breaks/DNA-protein cross-links between GLC4 and GLC4/ADR after exposure to ADR differed; these differences were compatible with differences in the distribution of the various types of DNA damage induced in the cell lines due to an altered ADR-topoisomerase II interaction. In this human small cell lung carcinoma cell line the resistance is multifactorial with decreased intracellular ADR levels, increased DNA repair, and altered ADR-topoisomerase interaction.

Carcinoma, Small Cell↗
PubMed1987

Twice weekly vindesine, a phase II study in lung cancer.

Vindesine 1.75 mg/m2, twice weekly for 2 weeks followed by 2 weeks rest, was given to 26 lung cancer patients. In 6 patients a partial response was seen (23%). Neurotoxicity was present in 15 patients after 1 course; in 6 patients this was the reason for stopping therapy. This regimen has no advantage over weekly vindesine.

Drug Administration Schedule↗
PubMed1987

Long-term survival after vinblastine, bleomycin, and cisplatin treatment in patients with germ cell tumors of the ovary: an update.

Thirteen patients with a malignant germ cell tumor of the ovary have been treated with a combination of vinblastine, bleomycin, and cisplatin (VBP). In 12 patients a complete remission was reached, which was maintained in 10 of these patients. One patient with large tumor residues and a partial remission became CR after surgery. The tumor recurred in 2 patients after 6 and 27 months. Overall, 11 of these patients are in long-term remission, from 14 to 84 months after the start of treatment. VBP is an effective treatment for malignant germ cell tumors of the ovary, even in patients with large tumor residuals.

Adolescent↗
PubMed1987

Phase II evaluation of trans-N3P3Az2(NHMe)4 (AZP) in non-small cell lung cancer.

Trans-N3P3Az2(NHMe)4 (AZP), an aziridinyl substituted cyclophosphazene, was evaluated in a phase II study in non-small cell lung cancer at a dose of .33 mg/m2 i.v. bolus every 3 weeks. There were no tumor responses seen. Cumulative bone marrow toxicity, comparable to other cyclophosphazenes, was noted. AZP is not useful for the treatment of NSCLC.

Adult↗