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R D Blumenthal

Publications and source records attributed to R D Blumenthal.

At least 55 records · Page 3Linked to original sources
PubMed1992

The presence of a concomitant bulky tumor can decrease the uptake and therapeutic efficacy of radiolabeled antibodies in small tumors.

We describe the effects that a concomitant large tumor mass can exert on the therapeutic efficacy of radioimmunotherapy against small tumors, using the nude mouse/GW-39 human colonic cancer model. The tumor uptake 7 days p.i. of i.v.-injected 131I-labeled anti-CEA MAb (NP-4) and anti-CSAp MAb (Mu-9) in small (less than 0.2 g) s.c. GW-39 tumors was approximately 3-fold lower in animals with a concomitant large (greater than 1.0 g) GW-39 tumor than in the absence of a large tumor. An inverse correlation between the mass of the tumor burden and the 131I levels in the blood was observed, indicating that a large tumor mass may act as a sink for the injected radiolabeled antibody. Increasing antibody protein dose did not reverse the reduced uptake in the small s.c. tumors. The therapeutic efficacy of a single 0.25-mCi injection of 131I-labeled anti-CSAp MAb Mu-9 towards intrapulmonary GW-39 metastases was tested in nude mice bearing either small or large GW-39 s.c. tumors. Over 80% of the animals with small s.c. GW-39 tumors survived 18 weeks after tumor transplantation, whereas less than 20% of the animals bearing large s.c. tumors survived past 13 weeks. Dosimetric calculations, based on biodistribution data over time, indicated that the presence of a large s.c. tumor mass may have decreased the radiation dose to the intrapulmonary tumors almost two-fold. However, the radiation dose to the blood was also decreased in the animals with the large tumor burden. Therefore, the animals with larger tumor burden may also have been able to sustain higher doses of the radioantibody. The presence of a large tumor mass can thus affect the biodistribution and therapeutic efficacy of radioiodinated antibodies. We suggest that bulky tumors can adsorb a considerable amount of the injected dose, thereby reducing the total amount of MAb available for binding to the smaller tumors.

Animals↗
PubMed1992

Dose escalation of radioantibody in a mouse model with the use of recombinant human interleukin-1 and granulocyte-macrophage colony-stimulating factor intervention to reduce myelosuppression.

BACKGROUND: In previous studies in a tumor-bearing hamster model, we demonstrated protection and rescue from radioantibody-induced hematopoietic toxicity by treatment with interleukin-1 (IL-1) before or after radioantibody treatment, as well as attenuation of duration of myelosuppression by administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). PURPOSE: The purpose of this study was to evaluate the ability of recombinant human IL-1 and recombinant murine GM-CSF to reduce myelosuppression and increase survival of non-tumor-bearing, female BALB/c mice while escalating the maximal tolerated dose (MTD) of radioantibody--the highest dose that results in no deaths. METHODS: We administered IL-1 for 7 days at 1 x 10(3) U twice a day and GM-CSF starting on the same day for 12 days at a dose of 0.5 micrograms twice a day, alone or in combination. The doses of iodine 131 (131I)-NP-4 IgG (anti-carcinoembryonic antigen monoclonal antibody) radioantibody used were 270, 340, and 370 microCi; the MTD in mice is 270 microCi. The 12-day schedule of cytokine administration was initiated at various times with respect to the radioantibody dose: on the same day; 6 or 3 days before radioantibody; or 3, 6, or 9 days after radioantibody. Treatment efficacy was measured by survival and white blood cell and platelet counts. RESULTS: A 25% increase to 340 microCi of radioantibody used alone resulted in 100% lethality within 25 days of treatment. The optimal cytokine schedule was a 12-day treatment with the combination of cytokines initiated 3 days before radioantibody. This treatment resulted in 100% survival and significantly reduced the magnitude and duration of hematopoietic toxicity. The increase in radioantibody dose resulted in an 85%-95% decrease in peripheral white blood cells and a 75%-85% reduction in platelets within 14 days of radioantibody administration. Further dose escalation to 370 microCi of radioantibody used alone (37% increase above the MTD) resulted in lethality to 12% of the mice. IL-1 or GM-CSF alone was minimally effective. CONCLUSIONS: These studies are the first demonstration that cytokines could be used to reduce radioantibody-induced leukopenia and thrombocytopenia and to escalate the tolerated dose of radioantibody by 25%. IMPLICATIONS: We plan to evaluate the potential therapeutic benefit of a 25% increase in radioantibody dose in a tumor-bearing mouse model.

Analysis of Variance↗
PubMed1992

Influence of antibody protein dose on therapeutic efficacy of radioiodinated antibodies in nude mice bearing GW-39 human tumor.

The biodistributions of three 131I-labeled murine monoclonal antibodies, NP-4 and Immu-14 anti(carcinoembryonic antigen), and Mu-9 anti-(colon-specific antigen p), were determined at antibody protein doses varying from 1 microgram to 1000 micrograms in nude mice with small (0.1-0.4 g) GW-39 human colonic cancer xenografts. For each antibody, the percentage of the injected dose per gram of tumor and tumor/nontumor ratios were constant over a wide protein dose range. However, at high protein doses (above 100 micrograms for NP-4 and Immu-14) the percentage of the injected dose per gram of tumor and tumor/nontumor ratios decreased. Assuming that the uptake of a control anti-(alpha-fetoprotein) antibody represents the amount of antibody that accumulates in the tumor nonspecifically (i.e., antigen-independently), it could be shown that for each antibody the amount of antibody protein that accumulates in the tumor specifically, increases linearly with the protein dose, reaching a plateau level at the highest doses tested. The growth inhibition of GW-39 tumor transplants in nude mice treated with 131I-labeled antibody at either low or high antibody protein dose was compared. These experiments indicated that, in this experimental model, enhanced antibody protein dose may decrease the therapeutic efficacy of radioiodinated antibodies. It is suggested that heterogeneous distribution at low protein dose, with intense localization around the blood vessels, may enhance the tumoricidal effect of radioantibodies.

Animals↗
PubMed1991

Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice.

The potential for radioimmunotherapy as an adjuvant treatment for early disseminated colonic cancer was investigated in an experimental lung metastasis model. Nude mice receiving intravenous injection with a suspension of human colonic cancer cells (GW-39) developed multiple (10-100) tumor nodules throughout the lungs, and more than 50% of the animals died of extensive tumor involvement within 5-10 weeks. Groups of eight or nine animals bearing 7-day-old tumor transplants were treated with a single intravenous injection of radioiodinated agents: either 0.15 or 0.30 mCi of whole IgG of the NP-4 murine monoclonal antibody (MAb) against carcinoembryonic antigen (CEA) or 0.15 or 0.30 mCi of whole IgG of Immu-31, an anti-alpha-fetoprotein (anti-AFP) MAb. Treatment of animals with 0.15 or 0.30 mCi of 131I-labeled NP-4 IgG 7 days after injection of tumor cells resulted in survival for 23 weeks after tumor implantation in four of eight and seven of nine animals, respectively. Microscopic examination revealed that over 90% of the lung tumor colonies had no evidence of surviving cells. Animals treated with 0.30 mCi of anti-AFP, an irrelevant MAb, survived 4 weeks longer than controls. Toxicity was evident in four of the 17 animals given 0.30 mCi of NP-4 IgG (specific) or anti-AFP IgG (irrelevant) MAb. These animals died within 1-3 weeks after radioantibody injection, suggesting that death was related to the radiation dose. None of the animals given 0.15 mCi of 131I-MAb died within this period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: an autoradiographic study.

The inaccessibility of radiolabeled antibody to poorly vascularized regions of solid tumors may reduce the therapeutic efficacy of these macromolecules. Theoretical mathematical models have predicted that increasing the protein dose administered would reduce the heterogeneity of radioantibody distribution. This investigation was undertaken to evaluate this hypothesis in experimental animal models. We have utilized the technique of macroautoradiography to demonstrate an increase in tumor penetration of the lower-affinity 125I-labeled NP-4 or higher-affinity Immu-14 anti-carcinoembryonic antigen (anti-CEA) mAbs into small (60.25-0.4 g) and large (0.8-1.5 g) GW-39 and LS174T human colonic xenografts, grown subcutaneously in the nude mouse, when 400 micrograms unlabeled antibody is administered simultaneously with 10 micrograms (100 microCi) radioantibody. Further increases in protein to 800 micrograms result in a reduction in total tumor uptake of the antibody. These in a reduction in total tumor uptake of the antibody. These differences in mAb distribution could be visualized as early as 1 day after antibody injection. Improved mAb penetration was also achieved for the Mu-9 anti-CSAp (anti-mucin) antibody using 800 micrograms unlabeled antibody. An irrelevant antibody (AFP-7-31) was found to be homogeneously distributed 3 days after injection, even at a low protein dose. Attempts to improve mAb penetration by increasing the protein dose in the GS-2 colorectal tumor, a model that has low NP-4 accretion as a result physiological barriers separating antibody from antigen, were not successful. These results suggest that a more homogeneous distribution of radioantibody can be achieved by carefully selecting a dose of unlabeled antibody to coadminister. Work is currently in progress to determine the effect of improved tumor distribution of radioantibody on the therapeutic potential of a single dose of radioantibody.

Adenocarcinoma↗
PubMed1991

Improved radioimmunotherapy of colorectal cancer xenografts using antibody mixtures against carcinoembryonic antigen and colon-specific antigen-p.

Radioimmunotherapy of GW-39 human colonic tumor xenografts grown in the hamster cheek pouch with 131I-labeled NP-4 anti-(carcinoembryonic antigen) (CEA) and 131I-labeled Mu-9 anti-(color-specific antigen-p) (CSAp) murine monoclonal antibodies, administered in combination, was more effective than using either antibody alone for tumor masses less than 0.5 cm3 in size. The antibody mixture had no therapeutic advantage for larger tumors. Therapeutic efficacy was determined by measuring the change in tumor size over time, quantifying the absolute number of tumors responding to radioantibody therapy, and determining the percentage growth inhibition of each treatment at various times after radioantibody administration. Several mechanisms are discussed to explain the improved tumoricidal effect of the antibody mixture noted in this model system, such as (a) the possibility that an antibody mixture could target a greater number of tumor cells, (b) the potential for antibody mixtures to provide better tumor distribution and (c) the possibility that antibodies administered in combination can increase the magnitude of tumor uptake of individual radioantibodies, thereby resulting in a greater radiation dose delivered to the tumor.

Animals↗
PubMed1991

Suppression of tumor vascular activity by radioantibody therapy: implications for multiple cycle treatments.

Autoradiographic analysis of the intratumor location of radioiodinated Mu-9 anti-CSAp antibody within 7 days of administration reveals a restricted distribution within 3-6 cell layers surrounding tumor vessels. Within 7-14 days after suboptimal radioantibody treatment (approximately 3000 rads), tumor vessel morphology and physiology are altered. Vessel number is reduced by 60-70%, vessel diameter is reduced, and remaining vessels are surrounded by fibrotic tissue. Vascular volume (VV) is reduced by 75%, blood flow rate (BF) is reduced 65%, and vascular permeability (VP) to an IgG is reduced by 60%. The change in VV is reversible by day 35 but BP and VP remain suppressed. Normal tissue (liver and lung) vasculature experience only small pertubations in physiology. These functional changes in tumor vessels reduce the magnitude of accretion of a second dose of radioantibody in tumor but not in normal tissue.

Animals↗
PubMed1990

Biological considerations for radioimmunotherapy.

We have examined three methods that may be useful for improving the therapeutic efficacy of antibody-targeted radionuclides. The principal limitation of radioimmunotherapy is myelotoxicity and thrombocytopenia. These are due mainly to the length of time the radioantibody remains in the blood. The clearance time of a radiolabeled immunoglobulin G (IgG) may be decreased by using fragments prepared from the IgG. Using murine monoclonal antibodies against human colonic cancer in an animal model with a transplantable human colonic tumor, we have shown that fractionated doses of 131I-labeled F(ab')2 fragments can provide similar tumoricidal activity as a single injection of IgG, but toxicity to the normal tissues is reduced significantly at this tumoricidal level. Thus, it is expected that improved tumoricidal activity may be achieved by further escalating the dose of F(ab')2 that is administered at each injection. An anti-antibody (second antibody) may also be used to remove an anti-tumor antibody rapidly from the blood. By allowing intact IgG to be used instead of fragments, a higher percentage of the radiolabeled anti-tumor antibodies may be concentrated in the tumor to provide higher tumor doses, yet toxicity to the normal tissues may be controlled by the removal of the radiolabeled antibody from the blood. We have shown that the injection of a second antibody 48 h after 131I-labeled anti-carcinoembryonic antigen antibody is given can reduce toxicity at least 2-fold without affecting the tumoricidal activity of the radioantibody. A third method for reducing the myelotoxicity of radioantibody treatment involves the use of cytokines to increase the production of white blood cells. For example, interleukin 1 may be given prior to, or sometime after, radioantibody treatment to increase the number of circulating white blood cells and thereby reduce myelotoxicity. Thus, modification of some of the biological factors limiting radioimmunotherapy may provide for improvements in cancer treatment with radiolabeled antibodies.

Animals↗
PubMed1990

Use of hematopoietic growth factors to control myelosuppression caused by radioimmunotherapy.

Therapeutically efficacious doses of 131I-antibody result in a loss in circulating white blood cells; the granulocyte population is suppressed by 80-85% and the agranulocytes by 60-65% following 2 mCi of 131I-antibody in hamsters. The administration of 100,000 units of human recombinant interleukin 1 24 h prior to radioantibody can prevent the loss in WBC from 1 mCi of radioantibody and reduce the loss from 2 mCi of antibody. Recombinant murine granulocyte-macrophage colony-stimulating factor is also a potent stimulator of myelopoiesis and may also be useful as a method of reducing radioantibody-induced myelosuppression. The tumor uptake of radioantibody in animals treated with recombinant interleukin 1 is reduced by 30% 1 day after injection of radioantibody but returns to levels seen in animals not treated with the cytokine at 96 and 168 h. Therapeutic efficacy is not compromised by doses of interleukin 1 used to prevent myelosuppression. Therefore, the use of cytokines will permit the use of higher doses of radioantibody for greater tumor therapy with less myelotoxicity than in the absence of cytokine treatments.

Animals↗
PubMed1990

Biological and clinical perspectives of cancer imaging and therapy with radiolabeled antibodies.

Cancer and other diseases that elaborate increased quantities of antigenic substances can be targeted with suitable antibodies labeled with radionuclides. Factors influencing this targeting include the nature, pharmacology, and physiology of the antibodies, the composition and physiology of the tissue targets, the character and linkage of the radionuclide to the antibody, the choice of radionuclide, and the method of administration of the radioimmunoconjugate. The current state of cancer imaging with gamma-emitting radiolabeled antibodies, using the more optimal Fab' antibody fragments conjugated with 99mTc and imaging by single-photon emission computed tomography, permits high detection rates (90% range) of tumors at or below 0.5 cm, thus disclosing lesions missed by conventional radiographic methods. In radioimmunotherapy, severe limitations are due to low antibody accretion in tumors (resulting in low target rad doses), inadequate conjugation of radiometals to antibodies, high red marrow toxicity, and human anti-antibody responses when foreign immunoglobulins are administered. However, radiosensitive tumors, such as lymphomas, have shown impressive clinical responses.

Antibodies, Monoclonal↗
PubMed1989

Influence of animal host and tumor implantation site on radio-antibody uptake in the GW-39 human colonic cancer xenograft.

The magnitude and kinetics of tumor uptake of a monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) in the GW-39 human colorectal cancer xenograft differ according to the animal used (nude mouse or hamster) and the site of implantation of the tumor within the animal (cheek pouch, leg muscle, subcutaneous or liver). Several physiological factors have been evaluated in an attempt to explain these differences in radio-antibody accumulation. The following observations have been made: (1) The animal host with the slower blood clearance of radio-antibody and the higher non-tumor tissue uptake has the higher tumor uptake; (2) the xenografts with a higher blood-flow rate, vascular volume and/or vascular permeability have a higher specific radio-antibody targeting; (3) the smaller, more viable tumors take up more radio-antibody per gram than the larger tumors; and (4) tumors with higher specific antigen content accrete more radio-antibody. These results are discussed in terms of the feasibility of clinical tumor imaging and therapy with radiolabelled antibodies.

Animals↗
PubMed1989

Comparison of therapeutic efficacy and host toxicity of two different 131I-labelled antibodies and their fragments in the GW-39 colonic cancer xenograft model.

The in vivo uptake, therapeutic potential, and host toxicity were evaluated for both the intact IgG and F(ab')2 fragment of 2 murine monoclonal antibodies (MAbs) directed against either carcino-embryonic antigen (CEA), called NP-4, or colon-specific antigen-p (CSAp), called Mu-9, in the GW-39 human colorectal carcinoma grown in the hamster cheek pouch. Mu-9 IgG and F(ab')2 were retained longer by the tumor than was the NP-4 IgG or F(ab')2, respectively. Localization of the two antibodies by micro-autoradiography revealed two distinct patterns. Mu-9 was seen densely around whole acini of tumor cells, whereas NP-4 was found around each individual cell, albeit less densely. The anti-tumor effects of 131I-labelled Mu-9 and NP-4 IgG were equal, but the therapeutic effectiveness of Mu-9 F(ab')2 was significantly higher than NP-4 F(ab')2, as measured by change in tumor size. A dose-dependent increase in host toxicity, as measured by change in body weight and change in peripheral white blood cells (p-WBCs), was observed with 0.5 to 3.0 mCi doses of 131I-IgG regardless of the MAb used. A 10-22% loss in body weight lasting 3-7 weeks and a 50-80% loss in pWBCs lasting 6-8 weeks were observed in these animals. In contrast, 3 x 2 mCi doses of 131I-NP-4 or Mu-9 F(ab')2 given at 3-day intervals, a schedule which was equally therapeutic to a single 2-mCi dose of 131I-IgG, resulted in only a 9% loss in body weight and a 50% loss in pWBCs that lasted only 1 week. This was followed by a complete recovery over the next 2-3 weeks. These data suggest that multiple doses of F(ab')2 can be as tumoricidal as a single dose of an intact MAb IgG, but significantly less toxic to the host.

Animals↗
PubMed1989

Cytotoxicity of receptor-mediated 16 alpha-[125I]iodoestradiol in cultured MCF-7 human breast cancer cells.

Therapeutic strategies using 125I-labeled steroid hormones are attractive in light of the estrogen dependence of many human breast cancers and the favorable microdosimetry resulting from 125I decay. We determined the uptake, specific estrogen receptor (ER) binding, and cytotoxicity of 16 alpha-[125I]iodoestradiol in cultured MCF-7 human breast cancer cells. The cytotoxicity of receptor-mediated 125I appears to be sufficient in MCF-7 cells to warrant in vivo experimentation. Furthermore, cytotoxicity not specific to ERs is minimal within the dose range necessary for ER saturation and specific cell killing. Competitive toxicity studies using nonradioactive 17 beta-estradiol demonstrate an unequivocal relationship between ER binding and clonogenic viability.

Animals↗
PubMed1989

Reduction by anti-antibody administration of the radiotoxicity associated with 131I-labeled antibody to carcinoembryonic antigen in cancer radioimmunotherapy.

Radiolabeled antibodies have been shown to have a therapeutic potential in tumor-bearing animal models. However, treatment with radiolabeled antibodies results in toxic effects to normal tissues, as monitored by losses in body weight and in peripheral wbcs. We have investigated the use of an anti-antibody, or second antibody (SA), as a means of reducing this toxicity. SA rapidly forms a complex with circulating radiolabeled antibody, causing an increase in the clearance rate of the radiolabeled antibody from the blood. Toxicity was significantly reduced in animals given the SA in comparison to the toxicity seen in animals given only the radiolabeled primary antibody (PA). The earlier the SA was administered, the lower was the toxicity. The therapeutic efficacy of radiolabeled antibody was not influenced by the administration of the SA given 48 hours after the PA. Thus, the controlled removal of circulating radiolabeled antibody by an anti-antibody can reduce the toxicity associated with radiolabeled antibody therapy without influencing the antitumor effect.

Animals↗
PubMed1989

[125I]iodotamoxifen cytotoxicity in cultured human (MCF-7) breast cancer cells.

We evaluated the uptake and radiotoxicity of [125I]iodotamoxifen (125ITAM) in MCF-7 human breast cancer cells in the presence or absence of excess non-radioactive estradiol (E2) or iodotamoxifen (ITAM). Studies in cells under wash-out conditions and in nuclei isolated from previously exposed cells showed that 125ITAM binds estrogen receptor (ER) and antiestrogen binding sites (AEBS) and has the capacity for considerable non-specific binding. The radiotoxicity of 125ITAM was a complex function related to ER content and/or function as well as interactions with ER, AEBS and non-specific binding. Addition of E2 or ITAM abolished ER mediated cell killing. ITAM but not E2 abolished AEBS mediated cytotoxicity. Non-specific binding accounted for considerable cytotoxicity. Although these studies confirm the radiotoxicity of nuclear bound 125I, multiple nuclear binding sites, variability in ER content and function and non-specific binding will all adversely influence ultimate clinical efficacy.

Breast Neoplasms↗
PubMed1988

Reduction of radioantibody-induced myelotoxicity in hamsters by recombinant interleukin-1.

Recombinant human interleukin 1 (IL-1) administered i.p. to tumor-bearing hamsters results in a dose-dependent 2- to 5-fold increase in total peripheral white blood cells. These levels remain elevated for 2 to 3 wk and then decline to base-line levels. Pretreatment of animals with similar doses of IL-1 prevents radioimmunotherapy-induced destruction of the radiosensitive hematopoietic system. Furthermore, recovery from radio-immunotherapy-induced myelosuppression is possible if animals are given IL-1 1 wk after radioimmunotherapy treatment. Thus, both protection and rescue from the hematopoietic damage associated with radioantibody treatment are feasible by pre- or posttreatment with IL-1.

Animals↗