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Biomedical subjects

B W Wessels

Publications and source records attributed to B W Wessels.

At least 37 records · Page 2Linked to original sources
PubMed1994

Tumor activity confirmation and isodose curve display for patients receiving iodine-131-labeled 16.88 human monoclonal antibody.

A study was performed to correlate activity quantitation derived from external imaging with surgical tumor specimens in patients who received radiolabeled monoclonal antibody. Patients were given I-131 labeled 16.88 human antibody and scanned 3-5 times by planar and/or single photon emission computed tomography imaging methods to acquire time-dependent activity data in tumor and normal tissues. A method also was developed to assess the heterogeneous activity distributions in tumor samples. Postsurgical tumor and normal tissue samples were subdivided into volume elements (voxels) of 0.5 cm x 0.5 cm x 0.05 cm thick, which were used to verify the activity quantitation computed by the conjugate view method and to appraise the heterogeneity of radiolabeled antibody uptake. Through the use of the measured voxel activities, along with the time-dependent activity curves available for the entire tumor specimen derived from imaging, the cumulated activity and absorbed dose for each voxel were uniquely determined. The calculated total absorbed dose values were color-coded as isodose curves and overlaid on a correlated computed tomographic image. In two patients, activity quantitation derived from external imaging correlated with surgical tumor resection specimens within +/- 11%. The tumor-absorbed dose heterogeneity ratio was found to be as high as 10:1, with an average tumor to whole body absorbed dose ratio of 4:1. The mapping of activity with a histologic overlay showed a good correlation among activity uptake, the presence of tumor, and antigen expression on a microscopic scale. The resultant isodose curves overlaid on correlative computed tomographic scans represent the first images obtained with actual radiolabeled antibody biodistribution data in patients.

Absorption↗
PubMed1992

Overview of animal studies comparing radioimmunotherapy with dose equivalent external beam irradiation.

As the field of radioimmunotherapy (RIT) continues to develop and looks increasingly promising, there is growing interest in the radiobiology of RIT. Recently, several investigators have conducted studies in animal models comparing the relative efficacy of RIT with dose equivalent external beam irradiation. Although these studies are the first of many to follow, the results are provocative and several patterns are suggested by the available data. The results of the studies are summarized and compared, and preliminary hypotheses that might explain the reported observations are discussed. In summary, results from studies comparing the efficacy of RIT with external beam irradiation have been variable and may be indicative of different underlying mechanisms. While the particular experimental model, design and methodology used to compare the efficacy of RIT with external beam irradiation are probably important influences upon subsequent observations, it appears that for a given tumor type, the size of the survival curve shoulder or alpha/beta ratio, and tumor doubling time are important determinants of the magnitude of the dose rate effect. When this effect is minimal, it is possible that other factors such as reoxygenation, the arrest of cells in G2, and selective targeting of tumor by radiolabelled antibody may explain, in part, the increased efficacy of RIT compared with external beam irradiation that has been observed in some systems.

Animals↗
PubMed1991

Radiobiologic studies comparing Yttrium-90 irradiation and external beam irradiation in vitro.

The purpose of this study was to compare the effectiveness of Yttrium-90 (Y-90) labeled antibody irradiation to 60Co external beam irradiation in vitro by colony formation assay. Two human colon carcinoma cell lines, LS174T, a high CEA producer, and WiDr, a low CEA producer, were exposed to specific activities of Y-90 labeled murine monoclonal anti-CEA antibody ranging from 2.5 to 30 microCi/ml for a fixed period of time. This resulted in calculated doses of 2.25 to 27 Gy and initial dose rates of 2.5 to 29 cGy/hr. Results were compared to similar doses of Y-90 labeled non-specific antibody, unlabeled specific and non-specific antibody, and 60Co external beam irradiation. External beam irradiation studies showed that WiDr, compared to LS174T, was more radioresistant with a larger shoulder to the survival curve, indicating a greater capacity for radiation-induced sublethal damage repair. WiDr was also more radioresistant to Y-90 antibody irradiation. When compared to external beam irradiation, Y-90 labeled antibody irradiation resulted in less cell killing by a factor of 2.4 for LS174T and 3.4 for WiDr. Unlabeled antibody had no significant effect on cell survival. Radiation-induced cell cycle delay experiments demonstrated that WiDr had less cell cycle delay (0.9 to 1.0 min/cGy) compared to LS174T (1.2 min/cGy) after single fraction external beam irradiation. Our results indicate that Y-90 low dose-rate irradiation is radiobiologically less effective in vitro than high dose-rate external beam irradiation by a factor of about 2.4 to 3.4. The results also suggest that the magnitude of this difference depends on the cell line's ability to repair sublethal radiation damage and the degree of cell cycle prolongation after irradiation.

Adenocarcinoma↗
PubMed1991

Study of the clinical thermoluminescent dosimeter in the direct measurement of radiation adsorbed dose for radioimmunotherapy.

One of the major obstacles facing radioimmunotherapy (RIT) is the lack of a device to measure directly tumor and normal tissue radiation absorbed dose. Calculations based on the clearance and imaging scans have several limitations; hence we design and fabricate a sheathed clinical thermoluminescent dosimeter (TLD) for the measurement of absorbed dose by implantation in humans. Preclinical studies are performed in nine normal rabbits. Complete blood count, body temperature monitoring, clinical observation and necropsy show no untoward effects from the TLD. Consistent bone marrow radiation doses are noted in the four rabbits receiving 131I-labeled monoclonal antibody A6H. By using up to 20 clinical TLDs in one sheath, it will be possible to determine macroscopic heterogeneities in organs undergoing RIT.

Animals↗
PubMed1991

Optimal antibody-radionuclide combinations for clinical radioimmunotherapy: a predictive model based on mouse pharmacokinetics.

A theoretical comparison was made of radioimmunotherapy (RIT) dosimetry estimates for eight radionuclides (90Y, 105Rh, 131I, 153Sm, 186Re, 188Re, 198Au, 211At) conjugated to IgG, F(ab')2, and Fab antibody forms. Antibody pharmacokinetics, derived from a nude mouse animal model were combined with appropriate physical data and S values to evaluate absorbed dose to a 0.5 kg centrally located tumor, total body and kidney. Radioimmunoconjugates of F(ab')2 with 90Y, 153Sm and 186Re were predicted to be the most promising for RIT.

Animals↗
PubMed1991

Dosimetry and pharmacokinetics of monoclonal antibody A6H with human renal cell carcinoma xenografts: single dose study.

Implantable miniature thermoluminescent dosimeters and conventional biodistribution analysis were used to determine the locally absorbed radiation dose delivered to three morphologically distinct human renal cell carcinoma xenografts (TK-39, TK-82 and TK-177C; N = 87) following a 50 microCi infusion of 131iodine-labeled monoclonal antibody A6H. Xenografts were clearly detected by radioimmuno-scintigraphy. Pronounced differences were noted among the three xenografts in MAb pharmacokinetics and in the locally absorbed irradiation doses which ranged from 2 to 5 cGy per injected microCi of 131iodine-labelled A6H.

Animals↗
PubMed1990

Current status of animal radioimmunotherapy.

Progress in animal radioimmunotherapy has been reviewed by highlighting 22 successful experiments using human xenografts in rodent models. Significant tumor growth delay has been observed in all experiments with five groups reporting tumor control 100 days post-tumor implantation. The radiobiological significance of these experiments is analyzed through a proposed framework for the comparison of radioimmunotherapy to external beam therapy in both animals and humans. The limits of applicability of animal modeling to the clinical setting are evaluated in terms of intrinsic radiosensitivity, tumor volume effects, tumor bed effects, and the host defense mechanism. A generalized strategy for the development of clinical radioimmunotherapy is proposed based on utilization of radioimmunotherapy as a boost therapy in combination with external beam radiation.

Animals↗
PubMed1990

Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies.

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5 or ZME018. Tumor regression was measured in 1 of 12, 9 of 10, and 12 of 12 compared to 0 of 10, 1 of 10, and 2 of 10 animals following administration of 50, 100, or 200 microCi 90Y-labeled P96.5 and ZME018, respectively. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3% 28 and 58 days following 100 and 200 microCi 90Y-radiolabeled P96.5 administration, respectively. In contrast, no average decrease in tumor volume was noted following 50, 100, or 200 microCi 90Y-labeled ZME018.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies.

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively. Shared cell surface antigens among neuroectodermally derived neoplasms provide a basis for exploration of human glioma radioimmunotherapy.

Animals↗
PubMed1990

Targeting and therapy of human glioma xenografts in vivo using radiolabeled antibodies.

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (uCi) of tumor activity per gram per 100 uCi injected activity compared to 4.5 uCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. Tumor dose found in normal organs is less than 20% of the tumor dose, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibodies QCI054 and ZME018, which define a tumor-associated and a second melanoma-associated antigen, respectively, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5, QCI054, and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Average absorbed doses of 3770 +/- 445 (mean +/- SEM), 2043 +/- 134, and 645 +/- 48 cGy in tumor, 353 +/- 41, 243 +/- 22, and 222 +/- 13 cGy in a contralateral control intramuscular site, 980 +/- 127, 815 +/- 41, and 651 +/- 63 cGy in liver, and 275 +/- 14, 263 +/- 11, and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 uCi 90Y-radiolabeled P96.5, QCI054, and ZME018, respectively. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5, QCI054, or ZME018. Striking tumor regression and prolonged survival were measured following administration of 90Y-labeled P96.5. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3 percent 28 and 58 days following 100 and 200 uCi 90Y-radiolabeled P96.5 administration, respectively. The time required to achieve four times the initial tumor volume was 6.1 +/- 0.9 days for buffer; 43 +/- 12 and 63 +/- 10 days for 50 and 100 uCi 90Y-radiolabeled P96.5; 7 +/- 2, 20 +/- 1, and 53 +/- 4 for 50, 100, and 200 uCi 90Y-radiolabeled QCI054; and 9 +/- 1, 13 +/- 1, and 29 +/- 3 days for 50, 100, and 200 uCi 90Y-radiolabeled ZME018, respectively. Average tumor regrowth failed to occur 180 days following administration of 200 uCi 90Y-labeled P96.5.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Yttrium-90 and iodine-131 radioimmunoglobulin therapy of an experimental human hepatoma.

Therapeutic trials were performed on the HepG2 human hepatoblastoma implanted s.c. in the athymic nude mouse. Animals were treated with polyclonal and monoclonal antiferritin and control antibodies labeled with either iodine-131 (131I) or yttrium-90 (90Y). Administration of 400 muCi of 131I-labeled polyclonal antiferritin or 300 muCi of 90Y-labeled polyclonal antiferritin significantly increased survival (P less than 0.001). There were no tumor cures with radiolabeled polyclonal antibody therapy. Animals treated with 200 or 300 muCi of 131I-labeled monoclonal antiferritin (QCI054) did not show increased survival compared to controls. Although 400 muCi of 131I-labeled QCI significantly prolonged survival, treatment resulted in no long-term survivors. Monoclonal antiferritin labeled with 90Y significantly prolonged survival of animals (P less than 0.001) at doses of 100, 200, or 300 muCi compared with untreated controls. Fifty % of the animals treated with 200 muCi and 75% of the animals treated with 300 muCi showed no evidence of disease at 140 days following treatment. Four hundred muCi of 90Y-labeled QCI proved toxic to the animals. Increased survival was accompanied by a decrease in tumor mitotic rate and increase in cellular polymorphism as determined by pathological examination. The radiation dose absorbed in the tumor correlated directly with tumor response following treatment. The absorbed dose in tumors for complete decay of the isotope ranged from 165 and 330 cGy at the periphery and center of small tumors for an administered activity of 200 muCi of 131I-labeled polyclonal antiferritin, to 7,573 and 12,400 cGy for 300 muCi of 90Y-labeled monoclonal antiferritin QCI.

Animals↗
PubMed1989

Radiobiological comparison of external beam irradiation and radioimmunotherapy in renal cell carcinoma xenografts.

Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice receiving single fraction external beam irradiation (SF-XRT), multifraction external beam irradiation (MF-XRT), or radioimmunotherapy (RIT). Thermoluminescent dosimeter(s) (TLD) and autoradiography were used to ascertain the average absorbed dose delivered and the degree of heterogeneous uptake of radiolabeled antibody for the RIT irradiations. For intravenous administered activities of 100, 200, 400, and 600 microCi of I-131 labeled A6H antibody, volume doubling times (VDT) and TLD absorbed dose measurements for each administered activity were 7 days (341 cGy), 38 days (383 cGy), 85 days (886 cGy) and no regrowth (1034 cGy), respectively. For SF-XRT irradiations of 500, 1000, and 1500 cGy, VDT times were 11, 62, and 103 days, respectively. MF-XRT of 4 X 250 cGy over a 2-week period yielded a VDT of 25 days. Marked peripheral activity deposition was noted on most autoradiographs from multiple tumor samples. These data suggest that an equivalent to superior tumor growth delay is obtained for absorbed doses delivered by exponentially decaying low dose rate radioimmunotherapy RIT compared to similar doses of acute dose rate XRT as quantitated by the TLD method.

Animals↗
PubMed1988

Direct dose confirmation of quantitative autoradiography with micro-TLD measurements for radioimmunotherapy.

Autoradiography has shown marked heterogeneous distribution of radioactivity in all ten radiolabeled monoclonal antibody/tumor combinations evaluated by our laboratories for radioimmunotherapy (RIT) in mice. Quantitative autoradiography was performed on two of these combinations (131I-B72.3/colorectal carcinoma and 131I-LYM-1/Raji B-cell lymphoma) to obtain a correlation of film density with radiolabeled antibody distribution. Through the use of sectioned mini-thermoluminescent dosimeter(s) (TLD) or micro-TLD, isodose curves were generated from the film gradient density lines. A computer program was written to compare theoretical absorbed dose calculations to measured micro-TLD values. First-order agreement was reached for both antibody/tumor systems: (a) B72.3/colorectal system--810 cGy measured/824 cGy calculated per 200 microCi injected and (b) LYM-1/lymphoma system--1,740 cGy measured/1,580 cGy calculated per 656 microCi injected (1 cGy = 1 rad). Additionally, the measured absorbed dose heterogeneity over a 500-micron length of up to 400% which suggests that the use of quantitative autoradiography is necessary in order to correctly determine the underlying radiobiological effects of RIT. Theoretical computer modeling based on similar autoradiographic activity distributions has also provided a convenient means of assessing absorbed dose variation patterns from other radiolabels such as 90Y.

Animals↗
PubMed1987

Irradiation of bilateral orbital lymphoma: a non-coplanar technique with case reports.

Bilateral synchronous involvement of the orbits by lymphoma is an uncommon event. Therefore, the irradiation techniques for this disease are not well refined. Depending on the technique used, one has to decide between underdosing the anterior segment of the orbit and the frequently involved lacrimal glands or to tolerate shield related in homogeneities in the range of 40 to 50% as well as higher doses to the midline structures, e.g. the optic chiasma. To avoid the above shortcomings we developed a technique by which half the prescribed dose is delivered by pairs of beams angulated in the transverse plane and the other half by pairs of beams angulated in the sagittal plane. Film dosimetry in a phantom confirms that the entire orbit, including its anterior portion, is well covered, the lens is protected, and the dose to the mid-sagittal structures is not increased. The dose inhomogeneity is in the range of 20% which represents a substantial improvement over alternative methods. Two irradiated patients with bilateral orbital lymphoma are presented with local control and no ophthalmic or other side effects as of last follow-up.

Adult↗
PubMed1986

Radiolabeled biomolecules with 186Re: potential for radioimmunotherapy.

Rhenium-186 has been theoretically determined to be among the best therapy radiolabels due to its unique half-life, particulate and gamma emissions and chelation properties. Traditionally, rhenium chelates have been synthesized by the tin reduction method at low pH which frequently produces denaturation of acid labile proteins. A comparative study has been carried out to assess three techniques of reducing 186ReO-4 in order to label biologically active macromolecules (i.e. human serum albumin (HSA), anti-human serum albumin antibody (HSA-Ab) and a monoclonal antibody to T-cells [T-101]). These experiments showed that stannous and dithionite reduction methods provide for an overall labeling yield of between 5 and 18% with an associated immunoreactivity of 12-40%. The hypophosphorous acid (H3PO2) reduction method, however, yielded no usable radiolabeled product. The preparation of 186Re-DTPA-HSA produced an 18.2% radiochemical yield (7.4 X 10(6) Bq/mg) and 40% retention of binding affinity. Using the stannous or dithionite reduction methods for the radiolabeling of HSA-Ab and T-101 resulted in a relatively low yield (9%), but the labeled product retained binding affinity of 12.25% with Protein A.

Antibodies, Monoclonal↗