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Biomedical subjects

E Boven

Publications and source records attributed to E Boven.

124 records · Page 7Linked to original sources
PubMed1986

Selective cytotoxicity of 125I-labeled monoclonal antibody T101 in human malignant T cell lines.

The radiolabeled anti-T cell antibody T101 can be used for specific tumor localization, but unlabeled T101 produces limited cytotoxicity in patients. We thus studied the in vitro cytotoxic effects of T101 labeled with 125I, a radionuclide known for its short-range, high-linear-energy electrons. We showed that 125I-T101 could be readily prepared at high specific activity with high immunoreactivity. Human malignant T cell lines HUT 102, MOLT-4, and HUT 78 were found to differ in the number of T65 determinants (the antigen recognized by T101) and the sensitivity to external x-ray radiation, which were of significance for the cytotoxicity of 125I-T101 in vitro. The cytotoxic effects of 125I-T101 were also found to be dose dependent and increased with exposure time under frozen conditions. As controls, unlabeled T101 had no cytotoxic effect, while free Na 125I or the 125I-labeled irrelevant antibody 9.2.27 exerted minor cytotoxicity. In HUT 102 and MOLT-4, more than 3 logs' cell killing was achieved within four weeks. Because considerable cytotoxicity was demonstrated in vitro by 125I-T101 on T65-positive malignant cells, and because low-dose 111In-T101 can be used successfully for tumor localization, future trials using 125I-T101 at high specific radioactivity may improve therapeutic results in patients with T65-positive malignancies.

Antibodies, Monoclonal↗
PubMed1985

Secondary screening of platinum compounds in human ovarian cancer xenografts in nude mice.

Five TNO platinum compounds were evaluated for antitumor activities in two human ovarian carcinoma tumor lines grown in nude mice. The most active drug, TNO-38, was investigated in five additional lines with a known range of sensitivity to cisplatin. None of the new compounds showed superior activity to cisplatin. The slightly lower activity of TNO-38 as compared to the parent compound was reproducible in all tumor lines. Besides the similarity in the antitumor activity, a remarkable correspondence in platinum distribution and retention at 24 hr of TNO-38 and cisplatin could be observed. Chromatographic analysis of the compounds in their injection fluids showed single peaks for TNO-26 and TNO-38. The degradation products of the latter drugs may have affected their activity and toxicity. These human ovarian cancer xenografts may offer a reliable screening model for selection of a cisplatin analog with a higher therapeutic index or without cross-resistance for treatment in ovarian cancer.

Adenocarcinoma↗
PubMed1985

Specific killing of human melanoma cells by 125I-labeled 9.2.27 monoclonal antibody.

The anti-melanoma antibody 9.2.27 localizes to melanoma cells when administered i.v. to melanoma patients, but high doses of this antibody alone have no specific cytotoxic effect in vivo. To determine whether radiolabeled antibodies would exhibit specific antimelanoma cytotoxicity in vitro, cell survival curves were established for NCl-N892 human melanoma cells treated with 125I-labeled 9.2.27 monoclonal antibody. The binding capacity per cell was 5 X 10(5) molecules of 9.2.27 immunoglobulin G, and the association constant of binding was 10(10) M-1. Antibody preparations with specific radioactivities of 9-80 microCi/micrograms were used. Colony-forming ability after in vitro exposure to 125I-9.2.27 was determined by a 1-h antibody incubation at saturating concentrations, washing, and cell freezing for various exposure durations. Colony survival was dose dependent, varying with the radioactivity per cell and the exposure time. The survival curves demonstrated no shoulder effect and had a 37% incremental survival dose of 0.5-0.9 X 10(5) decays/cell. Selective killing of melanoma cells was demonstrated in experiments where NCl-N417 lung cancer cells were mixed with the melanoma cells prior to antibody treatment. The NCl-N417 cells did not express the melanoma-associated antigen, were more sensitive to conventional external irradiation than were the melanoma cells, and could easily be distinguished from them by different growth morphology. In spite of a growth advantage for the melanoma cells in the clonogenic assay, the antigen-negative lung cancer cells selectively survived the treatment and were the only surviving cells after 15 days of exposure.

Antibodies, Monoclonal↗
PubMed1985

Comparative activity and distribution studies of five platinum analogues in nude mice bearing human ovarian carcinoma xenografts.

The antitumor activity of four new platinum analogues was compared at equitoxic doses to that of cisplatin in B10 LP/cpb nude mice bearing xenografts of human ovarian carcinomas. The two tumor lines used, MRI-H-207 and Pe, differ in histology, tumor doubling time, and sensitivity to cisplatin. Complete remission of MRI-H-207 was observed with cisplatin, carboplatin, iproplatin, and JM-40, while spiroplatin only gave growth delay. Cisplatin and carboplatin caused some growth delay of Pe, while JM-40, spiroplatin, and iproplatin failed to affect tumor growth. Platinum tissue distribution was also measured for each compound in groups of five to seven tumor-bearing mice. Platinum concentrations in the two tumors at 24 hr were similar for cisplatin and carboplatin, but differed for iproplatin, spiroplatin, and JM-40. Organ distribution was similar for each analogue, and concentrations were significantly higher in kidneys than in liver, except for iproplatin with comparable concentrations in these organs. Our findings show a good correlation between analogue activity in ovarian cancer in the clinic and that in MRI-H-207. Platinum concentrations in tumor tissue did not predict antitumor activity.

Animals↗
PubMed1984

Recovery from mitomycin C-induced hemolytic uremic syndrome. A case report.

Mitomycin C (MMC) is a cytotoxic agent that may induce a hemolytic uremic syndrome (HUS) with severe renal insufficiency. Of all reported patients with terminal renal failure only two survived with chronic hemodialysis. A patient with advanced gastric cancer in complete remission, who developed MMC-induced HUS, is reported; hemodialysis was necessary because of oliguria. Hemolysis subsided, and after addition of captopril renal function recovered partially. The patient is alive 6 months after discontinuation of hemodialysis. Recently she developed brain metastases. Symptoms of hemolysis did not recur. The pathogenesis and treatment of HUS are discussed.

Blood Transfusion↗
PubMed1984

Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess.

Conjugates of monoclonal antibodies with radioactive isotopes, drugs or toxins have great potential for specific radiolocalization and inactivation of tumor cells. Because the conjugation procedure may adversely alter the antibody, quality control procedures must be applied to determine important characteristics of the conjugated antibody. One such property is how much of the conjugated antibody is able to bind to the relevant antigen. Based on theoretical considerations, we have developed a binding assay for radiolabeled monoclonal antibodies in which the fraction of immunoreactive antibody is determined by linear extrapolation to conditions representing infinite antigen excess. This ensures that the true value of the immunoreactive fraction is obtained, as opposed to the apparent immunoreactive fraction determined under conditions of limited antigen excess. The described assay is based on a double-inverse plot of the binding data which may be considered a modification of the Lineweaver-Burk plot. We established the method using 125I- and 111In-labeling of the 2 monoclonal antibodies T101 and 9.2.27 which currently are undergoing radioimaging trials at the National Cancer Institute. For properly performed conjugation procedures, immunoreactive fractions of about 0.9 were obtained, but a prolonged chloramine-T reaction for 125I-labeling resulted in an immunoreactive fraction of only 0.6. Due to its principle of determining binding at infinite antigen excess, the present method is quite insensitive to variation in the actual amounts of cells and antibody used, as well as the incubation time. We therefore recommend it as a quality control procedure for radiolabeled antibodies. Under certain conditions, this procedure is also applicable for quality control of drug- and toxin-conjugated monoclonal antibodies.

Antibodies, Monoclonal↗
PubMed1984

Complete response of metastasized adrenal cortical carcinoma with o,p'-DDD. Case report and literature review.

This study concerns the history of a male patient with hormone-producing adrenal cortical carcinoma. Six months after resection of the primary tumor, lymph node metastases were detected and treatment with o,p'-DDD [1,1 dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane] (Lysodren/mitotane) was started. After 2 years, a complete histologically proven response was confirmed at laparotomy and is still sustained 2 years after the discontinuation of treatment. As a consequence of insufficient steroid replacement the patient suffered bouts of adrenal insufficiency. After 1 year of treatment, the measurement of the plasma levels of o,p'-DDD showed an accumulation of the drug. At that time, progressive major central nervous system toxicity occurred, which proved to be reversible on discontinuation of the treatment.

Adrenal Cortex↗
PubMedDate not supplied

Improved characteristics of a human beta-glucuronidase-antibody conjugate after deglycosylation for use in antibody-directed enzyme prodrug therapy.

Antibody-directed enzyme prodrug therapy (ADEPT) aims at the specific activation of relatively nontoxic prodrugs into active drugs at the tumor site. One of the enzymes described to be useful in ADEPT is human beta-glucuronidase (GUS), which is expected to have low immunogenicity in patients. A major obstacle for the use of GUS, however, is its rapid glycan-specific hepatic clearance. The carbohydrates of GUS have been modified by subsequent treatment with NaIO4 and NaBH4 to improve its retention in the circulation. The modification of GUS did not decrease the enzyme activity. In vitro it was demonstrated that a conjugate prepared with a pancarcinoma specific monoclonal antibody (mAb) 323/A3 and the modified enzyme (mGUS), when bound to tumor cells, was capable of complete prodrug activation. In vivo, the 323/A3-mGUS conjugate was cleared faster from the circulation of BALB/c mice (t1/2 = 9 h) than mAb 323/A3 (t1/2 = 32 h), but it was retained in the circulation much longer than an immunoconjugate prepared with native GUS (t1/2 = 24 min). In nude mice bearing subcutaneous OVCAR-3 tumors the distribution of 323/A3-mGUS was qualitatively comparable to that of mAb 323/A3. The 323/A3-mGUS conjugate showed specific localization in the tumor but to a lesser extent than mAb 323/A3 (2.7% vs 6.4% injected dose per gram at 1 day after iv injection). A favorable tumor-to-blood ratio of > 2 was observed for the conjugate at 7 days after administration, which is necessary for tumor-specific prodrug activation.

Animals↗
PubMedDate not supplied

FOLFOX3 in heavily pretreated patients with metastatic colorectal cancer.

BACKGROUND: The combination of oxaliplatin, 5-fluorouracil (5FU) and leucovorin (LV) has shown to be active and safe as first- or second-line chemotherapy for metastatic colorectal cancer (MCC). PATIENTS AND METHODS: The outcome of patients with MCC who had progressive disease after at least two lines of palliative chemotherapy and who were subsequently treated with oxaliplatin, 5FU and LV was reviewed. Patients received FOLFOX3 consisting of oxaliplatin (85 mg/m2) on day 1, LV (500 mg/m2) as a two-hour infusion on days 1 and 2, and 5FU (3000 mg/m2) as a 46-hour infusion starting on day 1 in a cycle of two weeks. RESULTS: A total of 28 patients were treated with a median number of 9.5 cycles (range 1-24) at a mean dose intensity of 73%. Six patients discontinued treatment due to toxicity, of whom three had sensory neuropathy grade 2. Six patients experienced grade 3 toxicity: nausea (1), vomiting (1), diarrhoea (1), leucopenia (2) and thrombocytopenia (1); grade 4 toxicity was not observed. Twenty-five patients were evaluable for response, of whom four achieved a partial response (response rate 14%, based on intention to treat). The median progression-free survival was 5.8 months and the median overall survival was 8.5 months. CONCLUSION: For heavily pretreated patients with MCC, the FOLFOX3 regimen is a fairly safe and effective treatment.

Adult↗
PubMedDate not supplied

Human tumor xenografts in the nude mouse and their value as test models in anticancer drug development (review).

In an attempt to increase the predictability of preclinical antitumor testing, the value of human tumor lines in immune-deficient nude mice is assessed by reviewing the relevant literature. This test model is rather elaborate due to the nature of the animal as well as test and evaluation procedure. However, it represents a realistic simulation of clinical drug treatment. This is demonstrated by (a) a good correlation of drug effects in the nude mouse with clinical results in the donating patient's tumor and (b) by a good predictability of a panel of human tumor lines for clinically effective drugs. In order to avoid clinical trials with inactive drugs and no therapeutic benefit for a large number of patients, the application of human tumor xenografts in anticancer drug development is warranted.

Animals↗
PubMedDate not supplied

Distribution and kinetics of 131I-labeled human IgM monoclonal antibody 16.88 in patients with advanced colorectal cancer.

Sequential immunoscintigrams were used to describe the relative distribution and kinetics of 8 mg 131I-labeled human IgM monoclonal antibody 16.88 in 20 patients with colorectal cancer. The results show that the initial activity was higher and the clearance rate was faster (P < 0.05) from the left ventricle and liver than from most organs. In bone marrow the reverse was observed (P < 0.05). The biological half-life of 131I(-16.88) in tumor tissue (range 35.4-47.5 h) was longer (P < 0.01) than that in normal tissue (30.2-41.9 h). The image contrast ratio between liver metastases and background increased from 0.8 to 1.3 and for lesions outside the liver from 1.1 to 1.6. The estimated effective dose equivalent was 0.12 mSv/MBq. A second infusion 2 weeks after the first with the addition of unlabeled 16.88 up to 1000 mg for improvement of tumor tissue uptake was not of clinical relevance.

Antibodies, Monoclonal↗