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S Rodenhuis

Publications and source records attributed to S Rodenhuis.

At least 145 records · Page 8Linked to original sources
PubMed1990

Neutropenic enterocolitis in a patient with ovarian cancer after treatment with high-dose carboplatin and granulocyte macrophage-colony stimulating factor (GM-CSF).

A 50-yr-old women is described with relapsed ovarian cancer. She developed neutropenic enterocolitis after treatment with high-dose carboplatin (1000 mg/m2) and granulocyte macrophage-colony stimulating factor (GM-CSF). The clinical features and the pathogenesis of neutropenic enterocolitis are discussed. This case is the first report of neutropenic enterocolitis associated with the treatment of carboplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Cellular protoonocogenes are infrequently amplified in untreated non-small cell lung cancer.

To examine a potential contribution of protooncogene abnormalities other than point-mutational activation of the K-ras protooncogene in the classification of non-small cell lung cancer, amplification of cellular protooncogenes was studied in 47 lung tumour specimens obtained at thoracotomy and in four lung tumour cell lines. The primary tumours included 21 adenocarcinomas, nine large-cell carcinomas, 13 epidermoid carcinomas, one carcinoid and three metastases of primaries outside the lung. The copy numbers per haploid genome of 11 protooncogenes in every tumour sample were determined: H-ras, K-ras, N-ras, c-myc, N-myc, L-myc, erbB, mos, myb, ncu (erbB-2) and ral amplifications. The c-myc gene was amplified 5-7-fold in two adenocarcinomas, the H-ras gene 3 5-fold in one adenocarcinoma, while the K-ras and the neu gene were amplified in lung metastases from a colorectal and a breast cancer primary respectively. None of the tumours with an amplified protooncogene simultaneously harboured a mutationally activated K-ras gene. We conclude that amplification of the investigated protooncogenes is a rare event in non-small cell lung cancer. In view of the two c-myc amplifications detected, a systematic study of c-myc expression levels in non-small cell lung cancers appears worthwhile.

Blotting, Southern↗
PubMed1989

Drug resistance.

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Antineoplastic Agents↗
PubMed1989

The molecular genetics of human lung cancer.

With the development of molecular biological techniques the search for genetic alterations in cancer cells has resulted in the beginning of a molecular description of cellular transformation. Most of these genetic changes occur in genes which have a role in the control of cellular growth and development, the proto oncogenes. In the last decade, it has become clear that the myc and ras oncogene families are important in the carcinogenesis of human lung cancers. The myc oncogenes are usually found to be altered in small cell lung cancer (SCLC), and these alterations appear to correlate with rapid growth and progression. Mutations in the Kras gene are specific for adenocarcinoma, a subclass of non small cell lung cancer (NSCLC). Kras gene mutations are closely associated with tobacco smoking, since all were found in adenocarcinomas from patients with a history of smoking. The erbB oncogene, which encodes the epidermal growth factor receptor, is often highly expressed in epidermoid carcinomas. The roles for other oncogenes, such as raf or myb, as well as those of "suppressor" genes remain to be investigated, but may be of paramount importance. The study of alterations in proto oncogenes may aid in the (sub)classification and diagnosis of lung cancer, and may yield useful prognostic information in the near future.

Carcinoma, Non-Small-Cell Lung↗
PubMed1989

Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma. A multicentre phase II study.

Twenty-four evaluable patients with metastatic melanoma have been entered in a multicentre Phase II study of two induction cycles of human recombinant interleukin-2 (rIL-2) 18 x 10(6) IU/m2/day continuous i.v. bolus on days 1-5 and days 12-17. Dacarbazine (DTIC) 850 mg/m2 i.v. bolus was given on day 26. The cycle was repeated at five weeks. Maintenance therapy was scheduled three weeks after the completion of the induction treatment, consisting of rIL-2 18 x 10(6) IU/m2/day for five days alternating with DTIC 850 mg/m2 i.v., every three weeks, for a total of 18 weeks. Median age was 44 years (range 23-80), and Karnofsky index was 100 (range 80-100). One patient had received prior chemotherapy with hydroxyurea and one patient had prior radiotherapy. Six patients responded (25%): two had complete responses (CR) and four had partial responses (PR). Stable disease (SD) was seen in five patients. Responses occurred in the following sites: liver 2/9 (22%), lung 3/14 (21%), skin 2/11 (18%), and lymph nodes 3/12 (25%). Duration of CR was 11+ and 13 months. PRs lasted 2, 5, 7, and 11+ months. Of note, time to progression in patients with SD was similar to that of responders: 4, 4, 11+, 11+, and 14+ months. Toxicity included fever, skin rash, fatigue, anorexia, and diarrhoea in most patients. Two patients had a weight gain of more than 10%. Hypotension requiring vasoactive agents or interruption of rIL-2 occurred in four patients, creatinine elevations WHO grade 1-2 in seven patients, and bilirubin elevations WHO grade 1-3 in six patients. One patient developed transient ventricular tachycardia. It appears that rIL-2 and DTIC in this schedule is feasible and effective, but not clearly superior to rIL-2 alone.

Adult↗
PubMed1988

Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung.

47 tumor samples, 45 of which were obtained at thoracotomy for non-small cell lung cancer were examined for mutational activation of the oncogenes H-ras, K-ras, and N-ras. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. ras gene mutations were present in nine of 35 adenocarcinomas of the lung (all K-ras), in two of two lung metastases of colorectal adenocarcinomas (1 x K-ras, 1 x N-ras) and in one adenocarcinoma sample obtained at autopsy (H-ras). All K-ras and H-ras mutations were in either position 1 or 2 of codon 12, while the N-ras mutation was in position 2 of codon 61. The potential clinical significance of K-ras activation was analyzed using the combined results of this and of our earlier study (S. Rodenhuis et al., New Engl. J. Med., 317: 929-935, 1987). Lung adenocarcinomas with K-ras mutations tended to be smaller and were less likely to have spread to regional lymph nodes at presentation. With a median follow up of 10 months, survival data are still immature. None of six adenocarcinomas of nonsmokers had a K-ras mutation and only one of four who had stopped smoking more than 5 years before. We conclude that mutational K-ras activation is present in about a third of adenocarcinomas of the lung and that the mutational event may be a direct result of one or more carcinogenic ingredients of tobacco smoke. Studies involving larger numbers of patients are required to confirm the association of K-ras activation with smoking and the inverse relation with tumor progression.

Adenocarcinoma↗
PubMed1988

Resistance to cisplatin and analogues: mechanisms and potential clinical implications.

In view of the important role of cisplatin (CDDP) in cancer chemotherapy, the frequent occurrence of resistance to the drug is a major clinical problem. The main cause for unresponsiveness of a tumor to CDDP is thought to be cellular drug resistance, which may be caused by (1) a decreased uptake of CDDP, (2) an increase in metallothioneins, (3) an increase in glutathione and/or glutathione-S-transferase, (4) increased DNA repair, or (5) increased tolerance to unrepaired lesions in DNA. Several mechanisms may be concomitantly operative. However, almost all data on CDDP resistance are derived from cell lines or experimental animal systems, and it is uncertain whether they are relevant for human tumors. Possible methods for overcoming CDDP resistance in cancer patients include the use of high-dose CDDP or carboplatin or of different formulations of platinum derivatives, the regional administration of CDDP, the inducement of hyperthermia, the depletion of glutathione by buthionine-S-R-sulfoximine (BSO), or the use of platinum analogues. The development of methods to detect and classify CDDP resistance in human tumor samples is urgently required for the development of modalities to overcome resistance.

Animals↗
PubMed1987

Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung.

To define the role of cellular oncogenes in human cancers, we studied the prevalence of mutational activation of ras oncogenes in untreated non-small-cell lung cancer. Genomic DNA was extracted from 39 tumor specimens obtained by thoracotomy and was examined for activating point mutations in codons 12, 13, and 61 of the H-ras, K-ras, and N-ras genes. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. The K-ras gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No ras gene mutations were observed in 15 squamous-cell carcinomas, 10 large-cell carcinomas, 1 carcinoid, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small-cell carcinoma. An approximately 20-fold amplification of the unmutated K-ras gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. We conclude that mutational K-ras activation may be an important early event in the pathogenesis of adenocarcinoma of the lung but that amplification of ras genes or mutational activation of H-ras or N-ras does not play a major part in non-small-cell lung cancer.

Adenocarcinoma↗
PubMed1987

Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate.

Because of a previously observed plateau of clinical response after long-term methotrexate (MTX) therapy for rheumatoid arthritis (RA), we investigated whether such treatment might lead to acquired resistance to the drug. We studied the activity of dihydrofolate reductase (DHFR) (the target enzyme of MTX) in peripheral blood mononuclear cells of 11 RA patients who had been treated with MTX for a median of 43 months. The enzyme levels were markedly increased compared with levels found in the cells of 6 RA patients treated with other slow-acting drugs. Quantitative dot-blot analysis of DNA from 7 of these patients showed no evidence of DHFR gene amplification. No correlation was observed between increased levels of DHFR and either response to therapy or to the weekly MTX dosage. Phytohemagglutinin-stimulated peripheral blood lymphocytes from 6 patients with increased levels of DHFR showed no evidence of MTX resistance in vitro. The increased DHFR levels may result from binding of MTX to the enzyme, which may block the normal degradation pathways; they do not appear to be a marker of impending drug resistance.

Adult↗
PubMed1987

Effects of methotrexate and of the "nonclassical" folate antagonist trimetrexate on human leukemia cells.

Twenty-five samples of fresh malignant cells of patients with acute leukemia (16 with acute myeloblastic leukemia, five with acute lymphoblastic leukemia, and four with chronic myelocytic leukemia in blast crisis) and of two patients with colon carcinoma were exposed for 1 hr to different concentrations of methotrexate (MTX) or trimetrexate (TMQ). In all samples, TMQ was at least one log more potent than MTX in inhibiting [3H]deoxyuridine incorporation into DNA. Cells relatively resistant in vitro to MTX also displayed decreased sensitivity to TMQ, although TMQ "resistance" was usually much less pronounced. In eight of the 25 leukemia samples, intracellular drug levels after exposure in vitro could also be measured. The intracellular levels of TMQ were 6 to 64 times higher than those of MTX, indicating that the difference in potency of these drugs may be related to the difference in intracellular accumulation. The intracellular levels of both agents varied widely and were not directly related to the degree of DNA synthesis inhibition. There was, however, a clear positive correlation between the intracellular ratio [TMQ]/[MTX] and the deoxyuridine incorporation after exposure to MTX. This observation suggests that 1) intracellular TMQ levels may be used as an internal standard to correct steady state intracellular MTX levels for variations such as cell size, and 2) in analogy to tissue-culture models, decreased intracellular accumulation of MTX may contribute to clinically encountered drug resistance.

Adenocarcinoma↗
PubMed1986

Development of an assay system for the detection and classification of methotrexate resistance in fresh human leukemic cells.

An assay system was developed for the detection and classification of methotrexate resistance in fresh human leukemic cells. Mechanisms of resistance to be identified were: overexpression of dihydrofolate reductase, decreased cellular uptake of methotrexate, decreased affinity of dihydrofolate reductase for methotrexate, decreased polyglutamylation of methotrexate, and low thymidylate synthase activity. The initial screening procedure utilizes 3H release after addition of [5-3H]-2'-deoxyuridine as a measure of intracellular activity of thymidylate synthase and of DNA synthesis; 3H release is assayed after 3-h incubations with methotrexate, trimetrexate, or gamma-fluoromethotrexate and after 4-h incubations with these agents followed by a 6-h incubation in drug free medium. The pattern of DNA synthesis inhibition and recovery under these two sets of conditions establishes the presence or absence of methotrexate resistance and allows a tentative classification of the resistance mechanism involved. In combination with determinations of dihydrofolate reductase activity, methotrexate titration studies, and the determination of intracellular drug accumulations in vitro, the system is readily able to classify CCRF-CEM human leukemia cell lines possessing well defined mechanisms of resistance. The findings in seven leukemia patients are also reported. Applying tentative reference values, four patients showed biochemical evidence of methotrexate resistance: two patients had only a transport defect, one patient had evidence of both a transport defect and low thymidylate synthase activity, and one patient appeared to have decreased methotrexate polyglutamylation. Application of the assay system in larger numbers of patients is feasible and is required to establish adequate reference values for the evaluation of biochemical-clinical correlates.

Adolescent↗
PubMed1986

Absence of oncogene amplifications and occasional activation of N-ras in lymphoblastic leukemia of childhood.

To examine whether determination of (1) the copynumber or restriction pattern of certain oncogenes or (2) the mutational activation of the N-ras gene might contribute to the risk classification of acute lymphoblastic leukemia of childhood (ALL), we investigated DNA isolated from lymphoblasts of untreated patients. Restriction enzyme analysis of cellular oncogenes was performed on DNA of 25 patients. No rearrangements could be demonstrated within or near the genes c-myc, c-myb, c-abl, bcr, c-Ki-ras, and N-ras. No amplifications of these genes nor of N-myc or c-Ha-ras were present. Eight of 21 patients were heterozygote for "rare" Ha-ras allelic restriction fragments that have been associated with an increased risk of developing a malignancy. These patients were clinically indistinguishable from patients lacking these fragments. The breakpoint cluster region (bcr) that is rearranged in all patients with Philadelphia chromosome positive chronic myeloid leukemia, was normal in all cases, including at least one patient with Philadelphia chromosome positive ALL. A 2.8 kb HindIII fragment of a hitherto unknown gene or pseudogene related to v-myb probably derives from the Y chromosome. Nineteen patients were examined for point mutations in the N-ras gene, using a novel synthetic oligonucleotide hybridization assay. In two patients activating point mutations were present, both in positions 1 of the 12th codon. Both patients were somewhat older than the others (16 and 11 years), had L2 morphology, and were shown to have high growth fractions of tumor in their bone marrow.

Adolescent↗
PubMed1985

Serum beta 2-microglobulin: a real improvement in the management of multiple myeloma?

Beta 2-microglobulin (B2-m) determinations in serum have recently been introduced as a method of stratifying patients suffering from multiple myeloma. Conflicting results from several studies prompted us to study retrospectively the correlation of B2-m with presenting features and disease stage, as well as the prognostic value of B2-m, in 87 myeloma patients. Significant correlations were found between B2-m and presenting features such as haemoglobin level, serum calcium level and total body myeloma cell mass. The strongest correlation existed between B2-m and serum creatinine (r = 0.68). B2-m did not discriminate between the different disease stages as defined by Durie and Salmon, nor between myeloma Stage IA and monoclonal gammopathy of undetermined significance (MGUS). Considered alone, B2-m was found to have prognostic value in terms of survival. This correlation disappeared after correction for serum creatinine level and tumour load (multivariate analysis). Furthermore, changes in tumour load during therapy were not reflected in changes in B2-m levels, thereby rendering B2-m levels invalid as tumour marker. Our findings indicate no value for B2-m determinations in the staging and follow-up of myeloma patients.

Creatinine↗