131I标记抗CD20单克隆抗体在荷瘤裸鼠体内动态分布的实验研究

目的:探讨131I-anti-CD20 McAb经瘤内注射后在荷人Burkitts淋巴瘤细胞系Raji细胞移植瘤裸鼠体内的动态分布。方法:131I标记物的标记采用IODO-GEN碘化标记;注射标记物后第1、3、7、15天将荷瘤裸鼠活杀,定标器测量并计算瘤组织、血液等12种器官或组织的瘤/非瘤(T/NT)比值以及%ID/g值(每克组织摄入注入量的百分数)。结果:131I-anti-CD20 McAb瘤内注射组血液及其他组织器官T/NT比值在给药后第1、3和7天均显著高于腹腔注射组和131I-IgG瘤内注射组(P<0.05);该组肿瘤%ID/g值在给药后第1、3和7天分别为后两组的1.4~17倍和1.7~3.7倍;各非瘤组织和器官的%ID/g值低于后两组。结论:131I-anti-CD20 McAb经瘤内途径给药可以使肿瘤获得最高的放射性药物摄取率和最高的瘤/非瘤组织放射性药物摄取比,为下一步运用该途径进行放射免疫治疗提供了实验依据。     

131I-G250McAb治疗荷人肾透明细胞癌裸鼠的实验研究

目的:研究131I标记的抗肾癌相关抗原G250单克隆抗体(131I-G250McAb)在荷人肾透明细胞癌裸鼠体内的分布,探讨应用131I-G250单克隆抗体治疗实验性人肾癌的可行性和有效性.方法:将标记好的131I-G250单克隆抗体1 mL/只(3.7 MBq)静脉注射荷人肾癌裸鼠体内,后分批处死裸鼠,测定每克组织摄...     

Radiolocalization of xenografted human lung cancer with monoclonal antibody 8 in nude mice

A monoclonal antibody (MAb) 8 [immunoglobulin G3 (IgG3)], directed against a Mr 48,000 human lung cancer-associated antigen, was radiolabeled with either 125I or 131I, and its biodistribution was studied in nude mice bearing human lung cancer (TKB-2) over a 7-day period. 125I-labeled MAb 8 increased its binding to the tumor during the period, while the binding of 125I-labeled control IgG3 declined after initial uptake. At Day 7, percentages of injected dose of 125I-labeled MAb 8 bound to the tumor rose to 7.4%, which was a 4.4-fold increase from Day 1 and 16-fold binding of 125I-labeled control IgG3 at the same day. Tumor:blood ratios became 2.7:1 at Day 7, and tumor:liver, tumor:spleen, and tumor:kidney ratios were more than 9:1. Normal organs showed no significant uptake of 125I-labeled MAb 8, compared with those of 125I-labeled control IgG3. A clear image of the xenografted tumor was obtained at Day 5, and it further improved at Day 7, when 60% of whole body radioactivity was localized to the tumor. Autoradiography of the mouse with tumor confirmed the excellent localization of 125I-labeled MAb 8 to the tumor, although the radioactivity of the tumor was not uniformly distributed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that most of the radioactivity was present at the tumor in the form of degraded immunoglobulin. MAb 8 has a potential usefulness in the diagnosis and treatment of lung cancer.     

Complete tumor ablation with iodine 131-radiolabeled disialoganglioside GD2-specific monoclonal antibody against human neuroblastoma xenografted in nude mice

The antibody 3F8, an IgG3 murine monoclonal antibody (MoAb) against disialoganglioside GD2, could target iodine-131 (131I) to established subcutaneous human neuroblastoma (NB) xenografts in BALB/c nude mice. 131I-radiolabeled MoAb (0.125-1 mCi) was injected iv. Tumor radioactivity over time was calculated from scintigraphy, and radiation dose to individual tumors was calculated. Tumor shrinkage occurred only with 131I-labeled 3F8, but not with nonradioactive 3F8 or radiolabeled irrelevant antibody. While the tumor of the control mice enlarged by tenfold, the treated tumor showed over 95% shrinkage by 12 days. Both the rate of shrinkage and duration of tumor response were dose dependent. Calculated doses of more than 10,000 rad could be achieved. Only those tumors that received more than 4,200 rad were completely ablated without recurrence. Recurrent tumors were not antigen negative or radioresistant. These results confirmed the prediction based on imaging studies that human NB xenografts could be effectively eradicated with the use of 131I-labeled MoAb 3F8 with tolerable toxicities.     

Radioimmunotherapy of experimental pancreatic cancer with 131I-labeled monoclonal antibody PAM4

We examined the therapeutic efficacy of ¹³¹I-labeled murine monoclonal antibody (MAb) PAM4 against human pancreatic cancers carried as xenografts in athymic nude mice. Animals bearing the CaPanI tumor (0.2 cm³) were either untreated or were given, ¹³¹I-labeled nonspecific Ag8 antibody. By week 7 mean tumor size had grown 16.5 ± 8.4-fold and 4.2 ± 2.5-fold for the untreated and ¹³¹I-Ag8-treated animals, respectively. In contrast, animals administered ¹³¹I-PAM4 exhibited marked regression of tumors to an average of 15% of initial tumor volume. Since most pancreatic cancer patients present with large tumor burdens, the limitation of ¹³¹I-PAM4 treatment with respect to initial tumor size was investigated in animals bearing tumors of approximately 0.5 cm³, 1.0 cm³ and 2.0 cm³. Significant extension of survival time (>3-fold increase) was noted for both the 0.5 cm³ and 1.0 cm^{3 131}I-PAM4-treated groups, compared to their respective untreated controls. Even in the group bearing large 2.0-cm³ tumors, survival was increased 2-fold over the control group. To further improve anti-tumor effects in large tumors, 2 injections of ¹³¹I-PAM4 were administered at a 4-week interval to animals bearing tumors of approximately 1.0 cm³. Significant extended survival was noted for the group receiving 2 doses when compared to the group receiving only 1 dose. Int. J. Cancer 71:660-667, 1997. © 1997 Wiley-Liss, Inc.     

Radioimmunoscintigraphy of human gastric carcinoma xenografts with 125I-labeled monoclonal antibody

A monoclonal antibody (GC 302) established in our laboratory, which was reactive with gastric carcinoma and other epithelial carcinoma but not with normal gastric mucosa or other malignant tumors of mesenchymal origin, was used to investigate the radioimmunolocalization of tumors. Various kinds of target cells (5 X 10(5)) were incubated with 125I-labeled GC 302, and radioactivity was determined with a gamma counter. It was shown that there was a 500- to 1,000-fold increase in counts for gastric carcinoma (NUGC-2, NUGC-4, MKN-28 and MKN-45) as compared to those of normal lymphocytes and about 100-fold increase as compared to melanoma or leukemia. These findings were consistent with those obtained from the study of immunohistochemistry using GC 302. An in vitro assay was also carried out using nude mice bearing gastric cancer and inoculated with 125I-labeled GC 302. There was a 2- to 3-fold increase in radioactivity in the tumor and a 4- to 5-fold increase as compared with the visceral organs. Although the tumor:blood ratio was relatively low, radioimmunoscintigraphy could be done successfully with the aid of computed radiography. We thus conclude that further testing of GC 302 is worthwhile to establish whether or not it is useful for radioimmunoscintigraphy of metastatic lesions of gastric cancer for possible clinical application.     

Pharmacokinetics of 99mTc(Sn)- and 131I-labeled anti-carcinoembryonic antigen monoclonal antibody fragments in nude mice

The biodistribution, radioimmunoimaging, and high pressure liquid chromatography activity profiles of 99mTc(Sn) and 131I-labeled anti-carcinoembryonic antigen monoclonal antibody fragments were compared. Nude mice, bearing specific (colon carcinoma, LS174T) and nonspecific (pancreatic carcinoma, MIA) xenografts were given injections of the respective radiolabeled antibody fragments and also of irrelevant 125I-labeled antibody fragments (MOPC-21). The animals were imaged at 24 h after being given injections, they were sacrificed, and biodistribution studies were performed. Results of the study showed high kidney uptake [48.6% injected dose (ID)/g +/- 8.1% (SD)] and low tumor uptake (1.5% ID/g +/- 0.6%) for 99mTc(Sn)-labeled fragments and higher uptake (4.4% ID/g +/- 0.6%) for 131I-labeled fragments, resulting in a higher localization index for the radioiodinated monoclonal antibody fragments. Imaging results showed good tumor visualization at 24 h after injection for the 131I-labeled fragments and poor tumor visualization with predominant kidney uptake for 99mTc(Sn)-labeled fragments. After radiolabeling, high pressure liquid chromatography analysis indicated that 131I was primarily associated with F(ab')2 fragments, whereas 99mTc was mostly associated with Fab' fragments.     

抗人肺腺癌单克隆抗体在荷瘤裸鼠体内的分布及肿瘤放射免疫显象

Biodistribution and radioimmunoimaging of monoclonal antibody, 5F11, against human lung adenocarcinoma (LTEP-a2) in tumor-bearing nude mice were studied. The binding rate of radioiodinated 5F11 with LTEP-a2, as determined by in vitro binding assay, was 27.64 +/- 5.01%, while the control was less than 5.0%, suggesting that 5F11 reacted specifically with LTEP-a2. Seventy-two, 96 and 120 hr after injection of 125I-5F11, the percentage of dose taken per gram tumor tissue was 4.84%, 6.29% and 6.60%, higher than those of all normal organs. From 48 to 120 hr on, the ratio of tumor to normal tissue (T/NT) in the liver, spleen, kidney, stomach and intestine was more than 2; T/NT in the lung was 3.1-4.7; T/NT in the blood increased gradually and was 1.87 at 96 after injection. Tumor location index was 4.16, while that of the normal tissue was only 1.21. These results showed that human lung adenocarcinoma xenografts in nude mice were specifically located by radioiodinated 5F11. Radioimmunoimaging was performed in tumor-bearing nude mice. The tumors were clearly visualized 72 hr after injection of 131I-5F11. Radioactivity was higher in tumor region than in other regions. The optimal imaging time was 72-96 hr after injection of radioiodinated 5F11.     

Therapeutic application of a radiolabelled monoclonal antibody in nude mice xenografted with human neuroblastoma: tumoricidal effects and distribution studies

Monoclonal antibody UJ13A radiolabelled with isotopes of iodine has been shown to selectively localize to human neuroblastoma xenografts. When 131I-UJ13A conjugates were given to nude mice at high doses (100-150 microCi), tumours temporarily disappeared, only to regrow. No selection for neuroblastoma cells that were UJ13A - negative was observed. Distribution studies on mice receiving radiolabelled UJ13A demonstrated the antibody is rapidly lost from the blood of animals. This cannot be accounted for by selective uptake into xenografts or any other mouse organ examined. We concluded there is a rapid equilibration of isotope between intra- and extravascular spaces in the animal. The rapid, biphasic loss of UJ13A from the blood of mice may explain why so little injected antibody can target to the human tumour xenografts.     

Therapy with unlabeled and 131I-labeled pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt's lymphoma xenografts.

Clinical trials of radioimmunotherapy (RIT) of lymphoma have produced frequent tumor regressions and remissions, but it has been difficult to determine to what extent these tumor responses have been due to antibody-specific targeted radiation, nontargeted radiation, and/or cytotoxicity mediated by the carrier monoclonal antibody (MoAb). In this report, RIT was studied in athymic nude mice bearing s.c. Raji human Burkitt's lymphoma xenografts using two different pan-B-cell MoAbs, MB-1 (anti-CD37) and anti-B1 (anti-CD20), which differ in isotype (and thus the potential for interaction with host effector mechanisms) and isotype-matched control antibodies either in the unlabeled state or labeled with 131I. When a single i.p. injection of 300 microCi 131I-labeled MB-1 (IgG1) was compared to treatment with unlabeled MB-1 or 300 microCi 131I-labeled MYS control IgG1 MoAb, an antibody-specific targeted radiation effect of RIT was seen. 131I-labeled MB-1 produced a 44 +/- 19% (SEM) reduction in tumor size at 3 weeks posttreatment, while unlabeled MB-1 or 300 microCi 131I-labeled MYS control IgG1 antibody treatment resulted in continued tumor growth over this period of time. In vitro studies demonstrated that MB-1 was incapable of mediating antibody-dependent cellular cytotoxicity using Raji tumor cell targets and human peripheral blood mononuclear cells. Similar to the MB-1 studies, treatment with 300 microCi 131I-labeled anti-B1 produced a 64% reduction in mean tumor size, while 300 microCi of control antibody resulted in a 58% increase in tumor size over the same 3-week period. In contrast to MB-1, however, unlabeled anti-B1 (an IgG2a MoAb which in vitro studies showed to be capable of antibody-dependent cellular cytotoxicity) also had a substantial antitumor effect. Indeed, 300 microCi 131I-labeled anti-B1 and unlabeled anti-B1 treatment (using an equivalent amount of total protein in the treatment dose) produced a similar specific reduction in tumor size. Increasing the radionuclide dose of anti-B1 to 450 microCi in another experiment did not produce a significant difference in tumor regression compared to a 300-microCi dose. These results suggest that the antitumor effects of 131I-labeled anti-B1 treatment were dominated by antibody-mediated cytotoxicity mechanisms, such that an antibody-specific targeted radiation effect could not be distinguished. In contrast, antibody-specific targeting of radiation was the dominant mechanism of tumor killing with 131I-labeled MB-1.(ABSTRACT TRUNCATED AT 400 WORDS)     

Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX,an intrinsic marker of hypoxia,in nude mice xenografted with human colorectal carcinoma

Carbonic anhydrase IX (CA IX) is frequently expressed in human carcinomas and absent from the corresponding normal tissues. Strong induction by tumor hypoxia predisposes CA IX to serve as a target for cancer diagnostics and therapy. Here we evaluated targeting properties and pharmacokinetics of CA IX-specific monoclonal antibody (MAb) M75. Binding parameters of (125)I-labeled M75, including equilibrium dissociation constant, hypoxia-related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of (125)I-M75 in nude mice bearing HT-29 human colorectal carcinoma xenografts with hypoxic pattern of CA IX expression was studied by measurements of radioactivity in dissected tissues and macroautoradiography of tissue sections. Pharmacokinetics of intravenously administered (125)I-M75 was described using a 2-compartment model. Blood clearance showed a distribution phase t(1/2)(alpha) = 3.4 hr and an elimination phase t(1/2)(beta) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, (125)I-M75 exhibited specific accumulation in xenograft, with a mean uptake of 15.3 +/- 3.6% of injected dose per gram of tumor tissue at 48 hr postadministration. Specificity of M75 localization was confirmed by low tumor uptake of control antibody. Altogether, our data demonstrate that M75 MAb is a promising tool for selective immunotargeting of hypoxic human tumors that express CA IX.     

Treatment of intracranial human glioma xenografts with 131I-labeled anti-tenascin monoclonal antibody 81C6

Lack of tumor specificity renders current modalities for treating malignant glioma ineffective. The administration of 131I-labeled monoclonal antibody (Mab) 81C6, which reacts with the glioma-associated extracellular matrix antigen, tenascin, to nude mice carrying s.c. human glioma xenografts has resulted in significant tumor growth delay and tumor regression. In this study, we evaluated the therapeutic efficacy of 131I-labeled 81C6 in athymic rats bearing intracranial human glioma xenografts, a more appropriate model for human gliomas. Mab 81C6, an IgG2b immunoglobulin, and an isotype-matched control Mab, 45.6, were labeled at 12.5-23.6 mCi/mg with chloramine-T. The Mabs were given i.v. at 1.25 and 2.5 mCi/animal for 131I-labeled 81C6, and 1.25 mCi for 131I-labeled 45.6 control. Therapeutic response was evaluated by survival prolongation using Wilcoxon rank sum analysis. Three experiments were done. No significant survival prolongation was found in the trial in which the average tumor size at the time of Mab administration was 60 +/- 14 mm3, two-thirds the size which causes animal death. In experiment 2, Mab was given at 16 +/- 14 mm3 average intracranial tumor volume. Statistically significant (P less than or equal to 0.005) survival prolongation was found for animals treated with 2.5 mCi 131I-labeled 81C6. In that experiment, male animals with intracranial xenografts had significantly shorter survival than females (P less than or equal to 0.005). When only female animals were used in the analysis, the 1.25-mCi 81C6 group also was found to have longer survival benefit (P less than or equal to 0.01). In the third experiment, only female animals were used and the tumor size at the initiation of treatment was 20 +/- 9 mm3. Highly significant survival prolongation again was found in both 1.25 (P = 0.001) and 2.5 mCi (P less than 0.001) 131I-labeled 81C6 groups. The estimated dose to intracranial tumors from 1.25 mCi of 131I-labeled Mab was 1585 rads for 81C6 and 168 rads for 45.6. Dose to other organs from 81C6 and 45.6 was similar, ranging between 31 rads to the brain and 734 rads to the bone marrow. However, normocellularity was observed in most marrow tissue examined microscopically. Three animals receiving the low dose (1.25 mCi 81C6) survived for more than 71 days with apparent cures. In conclusion, intracranial human glioma xenografts were treated successfully with 131I-labeled 81C6 but not control Mab.     

Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody

Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody. The pharmacokinetics of 131I-labeled monoclonal antibody in these patients were compared with those of 28 other patients receiving i.p.-radiolabeled monoclonal antibody for the first time without exogenous human anti-murine immunoglobulin, and who had no preexisting endogenous human anti-murine immunoglobulin antibody. Patients receiving i.v. human anti-murine immunoglobulin antibody demonstrated a rapid clearance of 131I-labeled monoclonal antibody from their circulation. The (mean) maximum 131I blood content was 11.4% of the injected activity in patients receiving human anti-murine immunoglobulin antibody compared to 23.3% in patients not given human anti-murine immunoglobulin antibody. Intravenous human anti-murine immunoglobulin antibody decreased the radiation dose to bone marrow (from 131I-labeled monoclonal antibody in the vascular compartment) 4-fold. Following the injection of human anti-murine immunoglobulin antibody, 131I-monoclonal/human anti-murine immunoglobulin antibody immune complexes were rapidly transported to the liver. Antibody dehalogenation in the liver was rapid, with 87% of the injected 131I excreted in 5 days. Despite the efficient hepatic uptake of immune complexes, dehalogenation of monoclonal antibody was so rapid that the radiation dose to liver parenchyma from circulating 131I was decreased 4-fold rather than increased. All patients developed endogenous human anti-murine immunoglobulin antibody 2 to 3 weeks after treatment.     

Experimental radiotherapy of murine lymphoma with 131I-labeled anti-Thy 1.1 monoclonal antibody

Monoclonal antibodies against the Thy 1.1 differentiation antigen are ineffective in the treatment of transplanted AKR T-cell lymphoma once a palpable tumor nodule is present, due to the inability of the host to eliminate antibody-coated tumor cells. To overcome this limitation, we have evaluated the use of 131I-labeled anti-Thy 1.1 antibodies for the therapy of established AKR/J SL2 lymphoma (Thy 1.1+) nodules growing in congeneic AKR/Cu mice (Thy 1.2+). In these experiments, 131I-anti-Thy 1.1 antibody specifically localized to a s.c. tumor with a mean of 6.5% of the infused dose per g of tumor at 24 h after infusion. The proportion of infused anti-Thy 1.1 antibody localizing to tumor was constant following antibody doses of up to 400 micrograms/animal. Antibody iodinated with up to 2 atoms of iodine per antibody of molecule maintained binding activity and localization to tumor equivalent to antibody labeled with less iodine. The concentrations of 131I-anti-Thy 1.1 in tumor would result in delivery of a mean of 1600 cGy to tumor following infusion of 500 muCi of 131I-labeled anti-Thy 1.1 antibody. In comparison, 500 muCi 131I-labeled irrelevant antibody would deliver a mean of 380 cGy to tumor. Treatment of animals with palpable tumor nodules with 500 muCi 131I-anti-Thy 1.1 led to regression of the tumor nodule in 44% of animals, significantly prolonged survival, and cured two of five of the animals treated prior to the development of metastatic disease. In contrast, unlabeled anti-Thy 1.1 led to tumor response in 6% of animals, and up to 1000 muCi 131I-labeled irrelevant antibody had no effect on tumor growth. Therapy was limited by the emergence of variant tumor cells lacking the target antigen and by bone marrow toxicity following 131I-labeled antibody doses of greater than or equal to 1000 muCi/animal. These studies demonstrate that 131I-labeled monoclonal antibodies can have a significant antitumor effect in a situation where unmodified antibody is ineffective.     

Radiolocalization of xenografted human malignant melanoma by a monoclonal antibody (9.2.27) to a melanoma-associated antigen in nude mice

A murine monoclonal antibody (9.2.27), directed to a Mr 250,000 glycoprotein-chondroitan sulfate proteoglycan complex, was radiolabeled with 125I and assessed for radiolocalization in tumor and normal tissues of normal and tumor-bearing nude mice. The 125I-9.2.27 localized in vivo preferentially in Mr 250,000 antigen-expressing human melanomas (FMX-Met, SESX) but not in low antigen-expressing tumors (LOX-L) xenografted in nude mice. The imaging index of tumor cells was positively correlated with the antigen density of the various melanoma cell lines as measured by flow cytometry. The nonspecific immunoglobulin RPC-5 of the same IgG2a subclass as 9.2.27 did not specifically localize to xenografts of melanoma. The total amount of 125I-9.2.27 accumulated in the tumor was directly correlated with tumor size. However, the specific radioactivity (cpm/g) in smaller tumors was higher than that in larger tumors. Nonspecific uptake and circulating antibody levels differed between normals and tumor-bearers. The organs of the reticuloendothelial system of normal mice accumulated more labeled antibody than did those of tumor bearers, and conversely, tumor bearers had higher levels of circulating labeled antibody in the blood than normals. The circulating labeled antibody in tumor bearers was still monomeric but had no detectable antigen-binding capacity.     

Tumor necrosis treatment of ME-180 human cervical carcinoma model with 131I-labeled TNT-1 monoclonal antibody

In contrast to normal tissues, many malignant tumors contain a high proportion of dead and dying cells. The loss of membrane integrity that accompanies cellular degeneration permits macromolecules, including antibodies, to freely enter the cell cytoplasm. Based upon these observations, it was hypothesized that monoclonal antibodies to intracellular antigens, which are integral structural components and are retained by degenerating cells, may be used to target a wide range of human malignancies. Previous studies by our laboratory utilizing these principles have demonstrated the feasibility of imaging four different histological types of human cancer in a nude mouse model, using monoclonal antibodies directed against insoluble intranuclear antigens. The present study describes the application of this approach, designated tumor necrosis treatment, for the radioimmunotherapy of transplantable ME-180 human cervical carcinomas in the nude mouse. Groups of tumor-bearing nude mice received three weekly treatments of 150 or 300 microCi of 131I-labeled experimental (TNT-1) or control (Lym-1) monoclonal antibodies. Detailed biodistribution data, dosimetric evaluations, and therapeutic results are presented to demonstrate the effective and preferential targeting of 131I-labeled TNT-1 monoclonal antibody within the tumor. In the experimental groups, the dose delivered to the tumor was sufficient to induce clinical regressions in 88% of treated animals, without evidence of toxicity to normal tissues. Complete regressions were obtained in 25% of the mice treated with high dose TNT-1. Microscopic examination of the implantation sites of these mice demonstrated the presence of acute radiation damage and residual keratin-positive tumor cells showing marked evidence of degeneration. Dosimetric data obtained over the 3-week treatment period showed that, unlike control treated mice, which received approximately 500 cGy each week, the experimental animals received increasing doses of radiolabeled antibody with each treatment (averages for weeks 1, 2, and 3: 1066, 2046, and 2476 cGy, respectively). In accordance with these data, enhanced imaging and therapeutic responses were observed with each therapeutic dose in the TNT-1-treated groups, compared with controls. These results indicate that TNT-1 therapy produces an ever expanding population of TNT-1-positive targets in the tumor as a result of the centrifugal killing of adjacent viable tumor cells. To help illustrate these results, a four-compartment model of the dose distribution kinetics of TNT-1 is presented for discussion with respect to the possible application of this method for the imaging and treatment of cancer in     

Chromosome findings in human neuroblastomas xenografted in nude mice

Chromosomes were successfully studied in 8 of 9 human neuroblastomas (NBs) xenografted in nude mice. Structural abnormalities in the short arm of chromosome #1 were found in 6 of the 8 tumors; these included nonreciprocal translocations and simple deletions. The breakpoints were distributed between 1p11 and 1p34, and all of them had lost the terminal portion of 1p (1pter----1p34). Double minutes (DMs) and homogeneously staining regions (HSRs) were observed in 7 tumors; 6 had either DMs or HSRs, and one had some cells with DMs and other cells with HSR. Only one tumor had neither DMs, nor HSRs. Our study revealed that structural abnormalities in the NB xenografts were essentially the same as those in the NB cell lines and fresh tumors reported previously, and that DMs and HSRs were seen in most NB xenografts as frequently as in NB cell lines.     

Effects of hyperthermia and iodine-131-labeled anticarcinoembryonic antigen monoclonal antibody on human tumor xenografts in nude mice.

BACKGROUND. Many studies have demonstrated synergistic interaction between hyperthermia and radiation. This study was undertaken to determine whether hyperthermia could enhance the effect of radioimmunotherapy (RIT) in the treatment of human colon adenocarcinoma xenografts in nude mice. METHODS. The experiments were conducted in two parts. During the first part of the study, preliminary information was obtained regarding the effect of various temperatures (41 degrees C, 42 degrees C, and 43 degrees C for 45 minutes) and iodine-131-labeled anticarcinoembryonic antigen (CEA) monoclonal antibodies (RMoAb) with administered activity ranging from 130 +/- 19 microCi to 546 +/- 19 microCi on tumor regrowth delay (TRD) and volume doubling time. This information was used in Part 2 of the study, which included four groups of mice: (1) a control group, (2) a group treated with hyperthermia, (3) a group treated with RMoAb, and (4) a group treated with a combination of RMoAb and hyperthermia. RESULTS. Maximum and significantly increased TRD was observed in the group treated with RMoAb and hyperthermia (slope, 0.057) compared with the control group (slope, 0.322), the hyperthermia-treated group (slope, 0.302), and the group treated with RMoAb alone (slope, 0.098). The ratio of the slopes between the groups treated with RMoAb and those treated with RMoAb and hyperthermia was 1.72. No correlation was detected between the percent of antibody uptake in the tumor and tumor regression in the groups treated with heat and RMoAb and those treated with RMoAb alone. CONCLUSIONS. The results of these experiments show that hyperthermia increased the effectiveness of iodine-131-labeled anti-CEA monoclonal antibodies against human colon carcinoma xenografts in nude mice. This study offers a rationale for combining hyperthermia and low-dose radiation produced from RIT in clinical practice.     

Radioimmunotherapy of the GW-39 human colonic tumor xenograft with 131I-labeled murine monoclonal antibody to carcinoembryonic antigen

We have investigated the therapeutic efficacy of a single injection of 131I-labeled murine mouse monoclonal antibody (NP-4) against carcinoembryonic antigen using the human colonic tumor xenograft, GW-39, grown in the cheek pouches of adult hamsters. Therapeutic efficacy was dependent on the dose of radioactivity, the specificity of the antibody for the tumor, and the size of the tumor when the radioantibody was administered. A dose of 1 mCi of 131I-labeled NP-4 given 1 day after tumor transplantation completely inhibited the growth of 6 of 11 tumors over a 12-week period, and histological evidence indicated that viable tumor was absent in the tissue remaining at the injection site. Lower doses (0.5 mCi) of 131I-labeled NP-4 inhibited tumor growth over 90% in comparison to untreated animals, but the tumors eventually resumed growth. Delaying the administration of radioantibody for 4 or 7 days after tumor transplantation significantly reduced the therapeutic efficacy. Although the same dose of 131I-labeled irrelevant immunoglobulin G also inhibited tumor growth, 131I-labeled NP-4 was generally 2-3 times more effective in reducing tumor growth than was the control IgG. There was a 13% loss in body weight within 7 days after treatment with 1 mCi, but all the animals regained their weight by day 14, indicating that the level of radioactivity was tolerated well. Dosimetric calculations predicted that over 14 days a dose of nearly 2400 rads was delivered to the tumors with 131I-labeled NP-4. These results confirm our previous studies that 131I-labeled antibody can effectively inhibit tumor growth, but suggest that radioantibody therapy is most effectively administered when there is a low tumor burden.