Effect of pre-irradiation on radiopharmaceutical localization in human colon tumor xenografts using mono- and bispecific monoclonal antibodies.

In previous investigations we found that pre-irradiation of a tumor can significantly increase site-specific accumulation of radiolabeled monoclonal antibodies (MAb). The aims of the present study were to compare the effects of radiation on the localization of conventional MAb and a bifunctional delivery system and to evaluate a new time-dose schedule. T380 human colon tumors in athymic nude mice were irradiated (60Co, 10 Gy single dose) and the antibodies were injected 2 hours later.

Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model.

The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs.

Prediction of tumor response to experimental radioimmunotherapy with 90Y in nude mice.

Purpose: To identify those factors that predict variability in tumor response to 90Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy.

Methods And Materials: Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with 90Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume.

Effects of proton irradiation on radiolabeled monoclonal antibody uptake in human colon tumor xenografts.

A major limitation of radiolabeled monoclonal antibodies (MAbs) for cancer imaging and therapy is their low accumulation within solid tumors. We, and others, have previously shown that pretreatment of a tumor mass with gamma radiation can increase the level of radiolabeled MAb at the tumor site. Unlike that of conventional radiation, the dose distribution of protons allows for increasing the dose to the cancer volume while reducing the normal tissue dose.

Association of intestinal peptide transport with a protein related to the cadherin superfamily.

The first step in oral absorption of many medically important peptide-based drugs is mediated by an intestinal proton-dependent peptide transporter. This transporter facilitates the oral absorption of beta-lactam antibiotics and angiotensin-converting enzyme inhibitors from the intestine into enterocytes lining the luminal wall. A monoclonal antibody that blocked uptake of cephalexin was used to identify and clone a gene that encodes an approximately 92-kilodalton membrane protein that was associated with the acquisition of peptide transport activity by transport-deficient cells.

Production and in vivo characterization of a bifunctional antibody (IVA039.1) with specificity for the mouse interleukin-2 receptor and vinca alkaloids.

The autoreactive T cell plays a pivotal role in the pathogenesis of type I diabetes in humans and in rodent animal models. Elimination or attenuation of these cells may provide a means to treat the disease. The use of antibodies directed to T cells has shown varying degrees of effectiveness in the treatment of autoimmune disease.

Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice.

A physiologically based pharmacokinetic model to describe the biodistribution of a specific monoclonal antibody IgG1 (ZCE025) and its fragments (F(ab')2 and Fab) and of a nonspecific IgG1 (MOPC21) in normal tissues and a human colon carcinoma xenograft (T380) in nude mice is developed. The model simulates the experimental data on the concentration of these four macromolecules in plasma, urine, heart, lung, liver, kidney, spleen, bone, muscle, skin, GI tract, and tumor. This is the first such model for macromolecules with specific binding.

Use of bremsstrahlung radiation to monitor Y-90 tumor and whole body activities during experimental radioimmunotherapy in mice.

Background: Large differences in uptake between tumors, even for the same size, frequently observed in clinical and experimental radioimmunotherapy (RAIT), make monitoring of uptake in individual tumors imperative in comparing protocols. 90Y, widely-used for RAIT, emits no gamma radiation and absorption of the beta particle in tissue makes its detection unsuitable for in vivo monitoring. We tested whether bremsstrahlung radiation, produced when betas are decelerated by nuclei, could be used to monitor tumor uptake.

Site-specific prodrug activation by antibody-beta-lactamase conjugates: regression and long-term growth inhibition of human colon carcinoma xenograft models.

Antibody-directed catalysis (ADC) is a two-step method for the delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug. An ADC system consisting of F(ab')-beta-lactamase conjugates and a cephalosporin derivative of the oncolytic agent 4-desacetylvinblastine-3-carboxhydrazide was investigated. The ability of the system to mediate antitumor activity was compared with that of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice.

Reversal of Vinca alkaloid resistance by anti-P-glycoprotein monoclonal antibody HYB-241 in a human tumor xenograft.

A panel of monoclonal antibodies (MAbs) to P-glycoprotein was developed by immunization of mice with multidrug-resistant human neuroepithelioma and neuroblastoma cells. All the anti-P-glycoprotein MAbs reacted with the extracellular portion of P-glycoprotein. The MAbs were examined for their ability to enhance accumulation of actinomycin D, vincristine, vinblastine, and doxorubicin in the human mdr1 transfectant cell line, BRO/pFRmdr1.

Radiolocalization of human small cell lung cancer and antigen-positive normal tissues using monoclonal antibody LS2D617.

The murine monoclonal antibody LS2D617, which reacts with an antigen associated with human small cell lung carcinoma (SCLC), was tested in preclinical models to assess its potential for specific targeting of tumors in human SCLC cancer patients. LS2D617 detects a cell antigen on the surface of cultured SCLC and neuroblastoma cell lines. Scatchard analysis of the binding of LS2D617 to NCIH69 SCLC cells indicates an affinity constant of about 1 x 10(8) M-1 and an epitope expression level of approximately 2 x 10(6) antigenic sites/cell.

[Photocoagulation in retinal branch vein occlusion (RBVO) (author's transl)].

54 cases of retinal branch vein occlusion, 19 of which received photocoagulation treatment, were reviewed to assess the value of photocoagulation in this disease. Our results suggest that the effect of photocoagulation in the treatment of macular edema is not convincing. This finding is in contrast to the main stream in literature.

[Diagnosis and treatment of choroidal haemangioma (author's transl)].

A report on 14 patients who were treated for clinically confirmed haemangioma by Xenon-photocoagulation between 1961 and 1978. With one single exception it was possible to eliminate the accompanying retinal detachment and to stop further growth of the tumor. In accordance with some cases already published and in contrast to the opinion of Witmer, photocoagulation is recommended as a simple and effective method for treatment of choroidal haemangiomas.