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Biomedical subjects

E Boven

Publications and source records attributed to E Boven.

At least 109 records · Page 6Linked to original sources
PubMed1990

Doxorubicin compared with related compounds in a nude mouse model for human ovarian cancer.

Eight human ovarian cancer lines grown in nude mice were used to compare the activity of doxorubicin, epirubicin, mitoxantrone and menogaril. The tumour lines were different in histological subtype, tumour doubling time and sensitivity to doxorubicin. The compounds were administered intravenously at the maximum tolerated dose twice with one week in between when tumours measured 50-150 mm3. Growth inhibition greater than 50% was obtained for doxorubicin in 8/8, for epirubicin in 4/8, for mitoxantrone in 5/8 and for menogaril in 2/8 tumour lines. In MRI-H-207, doxorubicin was the only drug able to induce complete remission. Compared with doxorubicin, mitoxantrone and menogaril were given in proportionally higher doses than those administered to patients, but did not result in superior antitumour activity.

Animals↗
PubMed1990

Human IgM monoclonal antibody 16.88: pharmacokinetics and distribution in mouse and man.

Human IgM monoclonal antibody (MAb) 16.88 recognizes an antigen strongly expressed by colon cancer tissue. We used 131I-labelled 16.88 for biodistribution and pharmacokinetic studies in nude mice bearing WiDr or NIH:OVCAR-3 xenografts. Serum half-life was 8 h. Maximum tumour uptake was between 1 and 8 h after administration and amounted to, respectively, 3% and 1% of the injected dose g-1 for WiDr and NIH:OVCAR-3 tumours. Half-lives in these tumours were approximately 24 h. Tumour to normal colon uptake ratios increased from 2.3 at 24 h to 17 at 5 days after injection. Simultaneously, pharmacokinetic studies were performed in patients with advanced colon cancer reactive with 16.88. They were injected with 5 mCi 131I-16.88 by intravenous infusion over 2 h. Serum half-life was 20 h with greater than 90% of the 131I bound to 16.88. Within 40 h 50% of the injected dose was excreted as free 131I in the urine. In one patient an accelerated clearance was found, possibly caused by pre-existing antibodies reacting with 16.88. None of the patients showed an immune response against 16.88 antibody. Immunoscintigraphy showed positive tumour localization in the majority of the patients, best visualized at later days. We conclude that 16.88 has tumour localization properties while its human origin accounts for the lack of immunogenicity.

Animals↗
PubMed1989

Palliative care for brain metastases of solid tumour types.

Prognostic factors for survival were analyzed retrospectively in 214 patients with brain metastases of the solid tumour type. The most frequent neurological signs and symptoms at diagnosis of cerebral involvement were headache-nausea-vomiting and focal weakness. Similar numbers of patients were found to have solitary metastasis and multiple lesions. Non-small cell lung cancer, small cell lung cancer, breast cancer, melanoma, and renal cell cancer comprised the majority of the primaries. Most patients received high-dose corticosteroids, while in a third, anticonvulsant agents were administered. Of 157 patients treated with radiation alone, or surgery with or without radiation, 110 experienced alleviation of symptoms or stabilisation of the disease. In 38 patients with a solitary lesion, craniotomy was carried out, either with or without postoperative radiation; the latter group showed the longest survival with a median of 37 wk. The remaining group of 73 patients with one brain metastasis had a median survival of only 15 wk. The 69 patients with multiple lesions who had been irradiated had a median survival of 15 wk, while that for 34 untreated patients was 7 wk. A short median survival of 11 and 13 wk, respectively, was observed in patients with concurrent progressive extracerebral disease and in those with progressive neurological symptoms regardless of treatment. It is concluded that in patients with a solitary brain metastasis without progressive extracerebral disease surgery should be considered the treatment of first choice aiming at a long-term survival with a good quality of life.

Adrenal Cortex Hormones↗
PubMed1988

Efficacy of the neuropeptide ORG.2766 in the prevention and treatment of cisplatin-induced neurotoxicity in rats.

In rats chronic systemic treatment with cisplatin results in a sensory neuropathy as evidenced by a reduction in the sensory conduction velocity in the sciatic nerve. Concomitant administration of the neurotrophic ACTH4-9 analog, ORG.2766, prevents the occurrence of the neuropathy. In addition, treatment with ORG.2766 stops further deterioration and improves recovery of an already established cisplatin-induced neuropathy. Furthermore, concomitant administration of ORG.2766 during a first cisplatin treatment period results in a better resistance against neurotoxicity in a second exposure period. Finally, ORG.2766 was shown not to hamper the anti-tumor effect of cisplatin in mice, carrying implanted tumor cells from a FMa human tumor line. These data are discussed in view of the potential clinical use of ORG.2766 in prevention and treatment of cisplatin-induced neuropathy.

Adenocarcinoma↗
PubMed1988

Preclinical phase II studies in human tumor lines: a European multicenter study.

In an attempt to increase the predictability and to extend the differential capacity of the anticancer drug development program the American National Cancer Institute has recently proposed the introduction of a screening system consisting of human tumor cell lines to select drugs in a disease-oriented fashion rather than by the previously applied drug-oriented strategy. Although this new approach offers great advantages, assay limitations can be identified in testing unknown compounds for antitumor activity in vitro. Human tumor xenografts grown in nude mice may play an additional role in the prediction of clinical activity and the assessment of the spectrum of activity of potential anticancer drugs, because they have a better relationship with the clinical situation of cancer treatment. In a European multicenter collaboration it has been proposed to use panels of human tumor lines from solid tumor types to study: the antitumor activity of three different drugs per tumor type; the reliability of 'preclinical' phase II studies by comparison of the obtained data with results of phase II clinical trials; the feasibility of this joint project, such as the methodology, the reproducibility of experimental data and the introduction of uniform activity criteria. If preclinical phase II studies in human tumor lines generate reliable results, this in vivo screening system will create a unique possibility to better identify promising clinical candidate compounds or analogs of conventional cytostatic agents as well as those tumor types likely to respond to the selected investigational drugs.

Amsacrine↗
PubMed1988

Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

Adult↗
PubMed1988

Potential advances in combination chemotherapy for advanced testicular cancer.

An interim analysis of the current EORTC studies in advanced testicular cancer indicates that (a) for low volume metastatic disease the addition of bleomycin (B) to etoposide (E) and cisplatinum (P) may not be necessary, and (b) for high volume metastatic disease the alternating schedule of PVB/BEP is not superior to treatment with BEP. Future studies will subdivide patients into 3 groups. Those with low volume metastatic disease will receive EP using 2 dose schedules for cisplatin. Those with high volume metastases will receive either BEP or etoposide, ifosfamide and cisplatinum (VIP). Those with ultra-high volume metastases will receive BOP/VIP, possibly randomised against another intensive chemotherapy schedule.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Combined radiation therapy and daily low-dose cisplatin for inoperable, locally advanced non-small cell lung cancer: results of a phase II trial.

The Free University Hospital in Amsterdam conducted a phase II trial on inoperable patients with non-small cell lung cancer (NSCLC) to evaluate the role of cisplatin as a radiosensitizer. Forty patients were entered into the study. Thirty-three patients were evaluable for response and 37 for toxicity. The regimen consisted of the daily administration of cisplatin 6 mg/m2 administered within 30 minutes after each radiation therapy session. The radiation therapy modality was a regimen of 300 cGy four times per week for 4 weeks with a 2-week split in between, administering a total dose of 48 Gy. The overall response rate was 65%; median duration of control of local disease was 7 months, and overall survival was 10.5 months. Toxicity was considered to be mild. The results appear similar to data using radiation therapy alone; however, the optimum dosing and timing of this combination therapy has not been determined and deserves further clinical studies.

Carcinoma, Non-Small-Cell Lung↗
PubMed1987

Phase II trial of combined radiotherapy and daily low-dose cisplatin for inoperable, locally advanced non-small cell lung cancer (NSCLC).

With the use of cis-diamminedichloroplatinum(II), cisplatin, to enhance the effect of radiation a combined modality approach was designed to treat patients with inoperable, locally advanced NSCLC. The regimen consisted of radiation doses of 300 cGy for 4 days every week for 4 weeks with a 2 week split in between. Each radiation dose was followed by an i.v. injection of cisplatin 6 mg/m2 within 30 min. Hydration consisted on an oral fluid intake of 2 L only, enabling the patient to receive the treatment on an outpatient basis. Of 40 patients entered into the study, 37 were evaluable for toxicity and 33 for response. Overall response rate was 65% and complete response rate 22%. Median duration of local control was 7 months. The majority of all patients (76%) eventually progressed at the primary tumor site, while in 16 patients relapse occurred in distant sites first. Median duration of overall survival was 10.5 months, whereas that of complete responders was 29.5 months. Generally, acute side effects were transient and did not require discontinuation of treatment. One patient presented with thrombocytopenia 4 weeks after treatment had been finished. His death of cerebral bleeding was likely to be related with his therapy-resistant malignancy. Of late side effects three patients showed disabling symptoms consisting of uncontrollable pulmonary infections in the presence of tumor in two patients, one patient had radiation myelopathy and another experienced vertebral collapse with distal paresis. The combination of radiation and daily low-dose cisplatin is a tolerable treatment modality with most benefit for patients reaching a complete remission. Intensification of the regimen is being planned in those patients with inoperable, locally advanced squamous cell lung cancer to reach a complete remission.

Adenocarcinoma↗
PubMed1986

Superior efficacy of trimelamol to hexamethylmelamine in human ovarian cancer xenografts.

A series of eight human ovarian cancer lines grown in nude mice were used to compare the activity of hexamethylmelamine (HMM) and N2,N4,N6-trihydroxy methyl-N2,N4,N6-trimethylmelamine (trimelamol). The tumor lines differed in histological subtype and growth rate. The drugs were administered i.p. at the maximum tolerated dose at alternate days. Differences in volume of treated and control tumors were endpoints of the study. The tumor lines varied widely in sensitivity to HMM and in four lines a T/C% below 25% was achieved. Trimelamol appeared to be more active than HMM and achieved a T/C below 25% in seven tumor lines. Thus far, the drug has demonstrated significant activity in a phase I trial in ovarian cancer patients. Comparative clinical studies of HMM vs trimelamol have not yet been performed.

Altretamine↗
PubMed1986

Monoclonal antibodies in cancer treatment: where do we stand after 10 years?

Monoclonal antibodies (MoAbs) with specificity to tumour-associated antigens have become increasingly available during the past years. Presently, they are being applied in various in vitro diagnostic assays. They have contributed to the knowledge of cancer biology to a large extent. The understanding of cell surface characteristics and antigenic phenotype of tumours has in particular influenced the approach in the treatment of leukemias and lymphomas. From successful tumour localization in patients by gamma-emitting radio-labelled MoAbs it became clear, that these proteins offer a unique possibility to target therapeutic agents to tumour sites. The mere administration of MoAbs did not result in sufficient clinical benefit, but with proper precautions high doses of murine antibody were well tolerated. In order to use MoAbs as a carrier system, various toxins, cytostatic drugs, or radionuclides have been conjugated to these proteins. Thus far, specific problems were encountered not only associated with the immunoconjugate itself, but also to its fate in the patient. With regard to the substantial knowledge on the use of MoAbs in vivo obtained from animal tumour models, immunoscintigraphy in patients, and phase I serotherapy trials, we will undoubtedly determine the optimal conditions required for a conjugated anti-tumour agent to achieve enhanced cytotoxicity without increased side-effects. Preliminary results with high doses of 131I-labelled MoAbs in patients having tumour lesions expressing relevant antigens encourage further studies with immunoconjugates in cancer treatment. While much work needs to be done to further define the role of MoAbs as a new treatment modality in malignancies, this area of immunotherapy deserves great emphasis for the development of effective conjugates for future patients.

Animals↗