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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2, in order to study antibody distribution, pharmacokinetics, dosimetry, toxicity, tumor targeting, and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients, doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions, two mixed and minor responses, and one no response), while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted, and only myelotoxicity accompanied therapeutic doses, with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi, which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg), 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs, suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.
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PMID:Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody. 206 51

Combination chemotherapy remains the major current treatment of non-Hodgkin's lymphoma. B-cell lymphoma often has tumor-specific surface immunoglobulins called idiotypes. Clinical trials using murine monoclonal anti-idiotype antibodies as a targeting approach have shown some success. I describe a novel concept of using idiotype-specific peptides as an alternative targeting approach for the treatment of B-cell lymphoma. In brief, octapeptides that bind to the surface idiotype of the B-cell lymphoma are isolated from a large synthetic peptide library (10(6) to 10(7) peptides). Once the sequence of a tumor-specific octapeptide ligand is defined, large quantities can be synthesized and conjugated with a radionuclide (such as iodine 131). This should permit highly specific destruction of lymphoma cells that bind the labeled peptide. The theoretic advantages of this approach over the previous use of anti-idiotype antibodies are addressed.
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PMID:Treatment of B-cell lymphoma using peptides. A novel concept. 834 78

The method of counterflow centrifugal elutriation (CCE) facilitates the non-invasive separation of proliferating cells into the progressive stages of the cell division cycle. We present here detailed protocols for the separation of primary lymphocytes and lymphocytic cell lines including Jurkat, a mature human T-cell line, Ramos, a human B-cell line, WEHI-231, a murine B-cell lymphoma, and stimulated human peripheral T-cells into progressive stages of the cell division cycle by counterflow centrifugal elutriation. Protocols for using the elutriator to concentrate large volumes of cells prior to separation, the preparation of highly enriched lymphocyte populations at progressive stages through the cell division cycle and conversion parameters from low to high volume rotors are described. Simple dual-staining methods of BrdUrd incorporation and propidium iodide staining for DNA content and subsequent flow cytometry are detailed. Together with [3H]thymidine incorporation data these provide a very accurate determination of cell cycle position of the separated populations.
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PMID:Separation by counterflow centrifugal elutriation and analysis of T- and B-lymphocytic cell lines in progressive stages of cell division cycle. 913 27

CD22 antibodies (Abs) bound to B-cell lymphomas are known to be internalized and catabolized rapidly. Therefore, it would be expected that use of CD22 as a target for radioimmunotherapy should be enhanced by the use of "residualizing" radiolabels, which are trapped within the cell after catabolism of the Ab to which they had been conjugated. Our study was intended to evaluate this hypothesis using Ab LL2. In initial experiments, we found that LL2 binding was strongly temperature dependent, with approximately 15-fold greater binding at 37 degrees C than at 0 degrees C. A series of experiments suggested that this difference is due to a conformational change in the antigen at low temperature, so that the LL2 epitope is partially blocked. In vitro, residualizing labels-including 125I-dilactitol tyramine and 111In-DTPA-were retained by cells much longer than a conventional iodine label. In vivo, residualizing labels also showed a marked advantage in terms of uptake by Ramos B-cell lymphoma xenografts in nude mice. However, the absolute Ab uptake by xenografts was quite low, in comparison with results obtained with many carcinoma xenografts, which appears to be due in part to vascular properties of the B-cell lymphoma xenografts.
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PMID:The advantage of residualizing radiolabels for targeting B-cell lymphomas with a radiolabeled anti-CD22 monoclonal antibody. 913 80

We found that the mouse B cell lymphoma 38C13 underwent apoptosis in vitro when deprived of iron by three independent methods: (1) exposure to a synergistic pair of rat IgG monoclonal antibodies against the mouse transferrin receptor; (2) exposure to the iron chelator deferoxamine (DFO), and (3) exposure to a defined culture medium without any added iron (iron-poor medium). When each antibody was present at a concentration of 5 micrograms/ml, the number of living cells declined to approximately 25% after a 24-hour incubation. After 48 h, there were no surviving cells. When DFO was present at a concentration of 10 microM, the effects were similar, but delayed by 24 h. when iron-poor medium was used, the effects and kinetics were similar to those seen with antibody treatment. For each method of iron deprivation, the reduction in cell viability correlated with the development of apoptosis, as assessed by DNA fragmentation analysis and propidium iodide staining. Electron microscopy studies provided additional confirmation of apoptotic cell death. The addition of 500 microM ferric citrate completely prevented apoptosis for each of the three methods of iron deprivation. These studies provide new and compelling evidence to support the view that iron deprivation can specifically induce apoptosis and serve to strengthen the rationale for further studies of iron deprivation as a form of cancer treatment.
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PMID:Direct evidence that iron deprivation induces apoptosis in murine lymphoma 38C13. 925 29

Upon transforming growth factor-beta (TGF-beta) treatment, Ramos cells, a B-cell lymphoma cell line, undergo apoptosis, as measured by annexin V labeling, DNA fragmentation, and propidium iodide staining. Apoptosis could be observed by 24 h after TGF-beta exposure and occurred before the development of a significant blockage of cell cycle progression. TGF-beta-mediated apoptosis was also accompanied by a strong induction of caspase-3 subfamily activity. Incubation of cells with the caspase inhibitor Z-VAD.FMK at 20 microM, but not at 10 microM, prevented TGF-beta-induced apoptosis from occurring. By comparison, caspase-3 subfamily activity was 87% inhibited at 10 microM Z-VAD.FMK and completely inhibited at 20 microM. Because of TGF-beta's well-established role of regulating gene transcription, the mRNA levels for proteins associated with apoptosis (Fas- and Fas-associated proteins, Bcl-2 family members, IAP proteins, and I kappa B) were also studied. After 24 h of TGF-beta treatment, the most significant mRNA changes occurred with Bcl-XL (two-fold decrease) and Bik (twofold increase). TGF-beta treatment also resulted after 48 h in a fivefold decrease in Bcl-XL protein levels, based on immunoblotting analysis. Therefore, TGF-beta-mediated apoptosis involves the activation of caspases. In addition, TGF-beta transcriptionally regulates Bcl-2 family members, Bcl-XL and Bik, to further influence the apoptosis process.
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PMID:Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation. 966 22

The optimal use of radioiodinated internalizing monoclonal antibodies (mAbs) for radioimmunotherapy necessitates the development of practical methods for increasing the level of retention of 131I in the tumor. Lysosomally trapped ("residualizing") iodine radiolabels that have been previously designed are based mostly on carbohydrate-tyramine adducts, but these methods have drawbacks of low overall yields and/or high levels of mAb aggregation. We have developed a method using thiol-reactive diethylenetriaminepentaacetic acid (DTPA)-peptide adducts wherein the peptides are assembled with one or more D-amino acids, including D-tyrosine. Two such substrates, R-Gly-D-Tyr-D-Lys[1-(p-thiocarbonylaminobenzyl)DTPA], referred to as IMP-R1, and [R-D-Ala-D-Tyr-D-Tyr-D-Lys]2(CA-DTPA), referred to as IMP-R2, wherein R is 4-(N-maleimidomethyl)cyclohexane-1-carbonyl, were synthesized by preparing functional group-protected peptides on a solid phase, selectively derivatizing the lysine side chain with 1-(p-isothiocyanatobenzyl)DTPA or DTPA dianhydride (CA-DTPA), deprotecting other functional groups, and finally derivatizing the peptide's N-terminus so it contained a maleimide group. Radioiodinations of the peptides followed by conjugations to disulfide-reduced mAbs, carried out as a one-vial procedure, resulted in 32-89% overall yields, at specific activities of 1.8-11. 1 mCi/mg, with less than 2% aggregation. Two internalizing mAbs, LL2 (anti-CD 22 B-cell lymphoma mAb) and RS7 (an anti-adenocarcinoma mAb which targets EGP-1 antigen), labeled with this procedure exhibited a 2-3-fold better cellular retention in Ramos and Calu-3 tumor cell lines, in vitro, respectively, compared to the same mAbs radioiodinated with the chloramine-T method. The rationale for the new approach, syntheses, radiochemistry and in vitro data are presented.
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PMID:Labeling of monoclonal antibodies with diethylenetriaminepentaacetic acid-appended radioiodinated peptides containing D-amino acids. 1007 72

We report the radioimmunotherapy of mouse B-cell lymphoma, BCL1, using a panel of anti-B-cell monoclonal antibodies (MoAb) (anti-CD19, anti-CD22, anti-major histocompatibility complex (MHC) II, and anti-idiotype (Id) radiolabeled with 131-iodine. When administered early in disease (day 4), the 131I-anti-MHCII MoAb cured tumors as a result of targeted irradiation alone, the unlabeled MoAb being nontherapeutic. In contrast, 131I-anti-Id, despite targeting irradiation and having therapeutic activity as an unconjugated antibody, protected mice for only 30 days; 131I-anti-CD19 and anti-CD22 were therapeutically inactive. Binding and biodistribution studies showed that the anti-Id, unlike anti-MHCII, MoAb was cleared from target cells in vivo and delivered 4 times less irradiation to splenic tumor. Treating later in the disease (day 14) increased tumor load and produced the expected reduction in therapeutic activity with the anti-MHCII, but surprisingly, allowed 131I-anti-Id to cure most mice. This unexpected potency of 131I-anti-Id late in the disease appeared to result from the direct cytotoxicity of the anti-Id MoAb, which was more active in established disease, in combination with targeted irradiation. We believe the ability of targeted irradiation and certain cytotoxic MoAb to work cooperatively against tumor in this way has important implications for the selection of reagents in radioimmunotherapy of B-cell lymphoma.
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PMID:The importance of antibody-specificity in determining successful radioimmunotherapy of B-cell lymphoma. 1038 18

The tumor-specific localization of an anti-CD74 Ab, LL1, was demonstrated in nude mice bearing xenografts of human B-cell lymphoma. This Ab, conjugated to radionuclides emitting Auger electrons, including 125I and 111In, was previously reported to kill tumor cells in vitro effectively and specifically. The cytotoxic potency of this Ab is due to its uptake and catabolism at a very high level, which also affected the Ab biodistribution experiments. Thus, Ab localization to the tumor was only detected if a "residualizing" radiolabel was used, meaning a label that is trapped within cells, usually within lysosomes, after catabolism of the Ab to which it was conjugated. Similar results were obtained with three different residualizing labels: 111In conjugated via the chelators benzyl diethylenetriaminepentaacetic acid (DTPA) or 1.4,7,10-tetra-azacyclododecane-N, N', N", N"'-tetraacetic acid (DOTA), or 131I-dilactitol-tyramine, a residualizing form of iodine. The Ab protein dose could be high, 0.5 mg/mouse, without causing a decrease in specific tumor uptake, probably reflecting the high capacity for uptake. Moreover, tumors of moderate size were found to cause rapid, specific removal of the Ab from the blood, also a result of catabolic processes. This induced blood clearance naturally affected the Ab localization experiments, but this factor could be circumvented by increasing the Ab protein dose. Using a different Ab, anti-(mature MHC class II), the ability of Ab to penetrate relatively large solid tumors was investigated. Complete saturation of antigenic sites was observed in tumors up to 0.3 g in size, but quite high Ab protein doses were required, 5.0 mg/ mouse. These results provide a rationale for attempting therapy with radiolabeled LL1.
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PMID:Localization of an antibody to CD74 (MHC class II invariant chain) to human B cell lymphoma xenografts in nude mice. 1094 3

Lymphomas are among the tumors most responsive to chemotherapeutic agents and radiation therapy. Despite chemotherapeutic and radiological advances, tumor cell resistance still remains a problem, and the toxicity of chemotherapy and radiation therapy limits their potential. Less toxic therapies for lymphoma have been continued to search for effectiveness. Since the discovery of the hybridoma technology by Kohler and Milstein in 1975, utilizing antibodies as targeted therapy for lymphoma has been investigated for many years. After 20 years of clinical trials, monoclonal antibody therapy of lymphoma enters the new millennium ready for 'prime time'. Investigators' early enthusiasm was dampened by problems with tumor targeting, HAMA, and allergic reactions, but important advances in molecular biology and chelation chemistry have led to new and improved reagents. Rituximab(IDEC-C2B8) has already been approved by the FDA in USA and the Ministry of Welfare and Labour in Japan for relapsed CD20-positive lymphomas and indolent B-cell lymphoma including mantle cell lymphoma, respectively. Ibritumomab tiuxetan and iodine-131 anti-B1 antibody have an excellent anti-lymphoma profile, and both appear to have higher response rates than rituximab. Results from the rituximab vs. ibritumomab tiuxetan phase III trial clearly favor the latter especially in %CR. Radiolabeled Lym-1, T101, LL2, and anti-Tac data will be forthcoming. Continued refinements of immunotoxins will establish their possible therapeutic role, and a variety of antibody conjugates including drugs, prodrugs, nonprotein toxins, and other agents, will continue to be studied in the clinic. Bispecific antibodies for lymphoma are also in early clinical testing. Over the next 10 years, many of the major advances in lymphoma therapy will be antibody-based.
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PMID:[Development of monoclonal antibody therapy for malignant lymphoma]. 1190 66


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