International journal of cancer. Supplement = Journal international du cancer. Supplement最新文献

Jun and fos oncoproteins form a complex which regulates transcription from promoters containing AP-I binding sites. The "leucine zipper" domain of both fos and jun is necessary for the formation of the heterodimer, but the role of specific leucine residues is unclear. We have used site-specific mutagenesis to examine the contribution of individual leucine residues to the formation of a stable fos/jun protein complex and the binding of this complex to the AP-I site. Mutation of a single leucine in either fos or jun had no effect on protein complex formation. Furthermore, mutations of two consecutive leucines in jun did not interfere with heterodimer formation; however, in the case of fos, two consecutive mutations resulted in an inability to form a heterodimer. Although mutagenesis of the first leucine of the heptad repeat had no effect on protein complex formation, this mutation in either fos or jun drastically reduced the affinity of the complex for DNA. Thus, both fos and jun contribute directly to the DNA binding potential of the heterodimer.

Quantitation from planar imaging and single photon emission computed tomography (SPECT) were compared in phantom studies and in patients receiving therapeutic doses of 131I-labelled anti-CEA. During the reconstruction of the data for SPECT quantitation attenuation correction and a correction for Compton scatter were used. The limitations of both methods were examined using the phantom studies and it was shown that practical SPECT quantitation could be achieved in patients given therapeutic doses of 131I-labelled anti-CEA, and furthermore, that SPECT appeared to give a more accurate estimate of the activity concentration.

The pharmacokinetics of intraperitoneal (i.p.) radiolabelled monoclonal antibody (MAb) was studied in 35 patients receiving 40 i.p. injections. Eleven patients received 131I-labelled MAb, 24 received 90Y-labelled MAb, and 5 patients received a second 131I MAb treatment after having developed human anti-mouse antibodies (HAMA). All patients had blood and urine isotope activity monitored for 5 days after MAb injection. The radiation dose to bone marrow from the vascular compartment in the marrow was calculated by applying the MIRD formula to the measured blood activity. In HAMA-negative patients, peak blood isotope activity was observed at 40 hr post injection with a mean of 26% and 21% of the injected 131I and 90Y activity respectively. Sixty-five percent of the injected 131I activity, but only 12% of the administered 90Y, was excreted in the urine. Myelosuppression limited the administered 131I and 90Y activities to below 160 and 20 mCi respectively. In patients receiving 131I labelled MAbs, the marrow is irradiated by MAb within its circulation, producing myelosuppression that can be predicted by applying the MIRD formula to the blood isotope activity. This is not true for 90Y-labelled MAbs, where bone absorption of yttrium (which cannot be measured in patients) is the dominant radiation source for bone-marrow irradiation. Patients with HAMA present clear 131I MAb rapidly with a decreased radiation dose to marrow and reduced myelosuppression. Giving patients intravenous antimouse immunoglobulin to clear 131I-labelled MAb absorbed from the peritoneal cavity could decrease the toxicity observed in these patients. Patients receiving 90Y DTPA-chelated MAbs are unlikely to benefit, as catabolized yttrium is not excreted, and is concentrated in liver, spleen and bone. On the other hand, the use of i.v. chelating agents as EDTA may scavenge non-protein-bound 90Y with increased excretion in the urine and less myelosuppression.

Lym-I is a murine IgG2a monoclonal antibody (MAb) that is B-cell specific but has greater avidity for malignant B cells when compared with normal B lymphocytes. It was originally produced by immunizing mice with nuclei of cultured cells from a patient with Burkitt's lymphoma. Ten patients with progressive refractory B-cell malignancies were treated with 131I-labelled Lym-I. Treatment with 131I Lym-I produced complete or partial remissions in 4 patients. Toxicity did not occur or was mild in most patients. The only significant complications included two instances of fistula secondary to necrotic lymphoma and one instance of hypotension. Human antimouse antibodies occurred in only 2 patients after multiple injections of Lym-I antibody. This experience was in contrast to treatment of B-cell malignancies with unconjugated Lym-I alone. Unconjugated Lym-I also caused no significant toxicity but was less effective than 131I Lym-I.

We describe a model for the evaluation of anti-tumour antibody specificity, using a human carcinoma-bearing colon segment. After resection of the human colon tumour, the supplying artery was cannulated and perfused with fresh frozen plasma and heparin. Continuous control of pressure, flow, temperature, pH and various metabolic parameters were performed after administration of 131I-labelled anti-CEA antibody. Highly differentiated adenocarcinomas of the colon showed a much higher antibody uptake than undifferentiated tumours. Between 3 and 7% of the injected antibody was found in the tumour tissue. Autoradiography showed non-homogeneous binding in the tumour tissue. The non-specific antibody perfusion showed no tumour binding. We conclude that the ex vivo perfusion of resected colon carcinomas can be used to measure the kinetics of binding and clearance of MAbs in tumour tissue by direct scintigraphy. The cellular biodistribution of the antibody can be documented by means of autoradiography.

In vitro tests were conducted using human T and B cell lines, as well as whole blood, to establish the usefulness of 2 murine monoclonal antibodies (MAbs), an anti-CD5 (Pan T) and a Pan B, for potential radioimmunolocalization and therapy. Both MAbs showed specificity for the cell line in question as tested by indirect immunofluorescence and radioimmunoassay. Assays carried out on whole blood showed 40-70% of the added activity of 111In-labelled Pan B antibody binding to B cells and 20-24% of 111In-Pan T antibody binding to T cells. The amount of internalised 111In-labelled Pan B was 6% of total amount at 24 hr indicating a slow internalisation process. These results should allow for in vivo targeting of normal and neoplastic B and T cells.