Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

DeNardo, Sally J.; Kukis, David L.; Kroger, Linda A.; O’Donnell, Robert T.; Lamborn, Kathleen R.; Miers, Laird; DeNardo, David G.; Meares, Claude F.; DeNardo, Gerald L.

doi:10.1073/pnas.94.8.4000

Cited by 92 publications

(89 citation statements)

References 25 publications

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“…Numerous papers have been published in the last few years on the potential advantages of treatment with RAIT and chemotherapy. 8,9,53,54 The possibility of combining RAIT with other small molecular-weight therapeutic agents, particularly those that affect tumor vascular biology or those that take advantage of unique aspects of tumor physiology, has become an active and exciting area of research for us.…”

Section: Discussionmentioning

confidence: 99%

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Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia

et al. 2001

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Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ-1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO 2 levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW-39 human colonic xenografts, we established that the median pO 2 was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240-Ci dose of 131 I-MN-14 anti-carcinoembryonic antigen immunoglobulin G, their median pO 2 declined from 26.1 ؎ 9.6 mmHg to 9.8 ؎ 3.9 mmHg (p < 0.001). Using the radiotracer 3 H-MISO that accumulates in hypoxic regions, uptake in GW-39, LoVo and LS174T s.c. human colonic tumors increased 3.0-to 4.2-fold from day 14 through day 28 post-RAIT, but uptake of 3 H-MISO in CALU-3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of 3 H-MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti-PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO 2 levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT-treated and SR4233-treated GW-39 were 3.56 ؎ 0.40 and 7.98 ؎ 2.50 cm 3 . When RAIT ؉ SR4233 were delivered on the same day, tumor size dropped to 2.78 ؎ 0.80 cm 3 . If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 ؎ 0.32 cm 3 (p < 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT-treated and SR4233-treated tumors were 1.14 ؎ 0.36 cm 3 and 3.65 ؎ 0.78 cm 3 , respectively. When RAIT ؉ SR4233 were delivered on the same day, size was 0.51 ؎ 0.174 cm 3 . If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 ؎ 0.07 cm 3 (p < 0.05). Similar results were obtained for LoVo, but not for CALU-3 tumors. Another hypoxic cytotoxin, NLCQ-1, was also more efficacious 2 weeks after RAIT, compared with same-day dosing. Thus, information on tumor hypoxia after radioantibody therapy could be important for ascertaining a window of opportunity when the surviving tumor regions are most responsive to hypoxic cytotoxins.

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Section: Discussionmentioning

confidence: 99%

“…The primary focus has been on the use of chemotherapy with RAIT. 8,9 An alternative combination therapy approach worth considering is the use of RAIT with an agent that is maximally effective within the physiologic environment of tumor tissue.…”

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confidence: 99%

Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia

et al. 2001

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“…A blood sample of 4 µl was obtained from the tail vein of each mouse, and samples from mice within a group were pooled and diluted 1:10000 in phosphate-buffered saline for red blood cell counts, 1:20 in 3% acetic acid for white blood cell counts and 1:100 in 1% ammonium oxalate for platelet counts. 18) Body weight change of mice was also monitored. Effect of HT on intratumoral distribution of A7 Radioluminograms (autoradiograms) of tumors were obtained to assess the effect of HT on the intratumoral distribution of A7.…”

Section: Methodsmentioning

confidence: 99%

“…6) Therefore, several kinds of strategies have been examined to improve its efficacy, including the use of biological response modifiers to increase tumor targeting of labeled monoclonal antibodies (mAbs), [7][8][9] the use of a pretargeting system to obtain a better therapeutic ratio to normal tissues 10,11) and combination with other therapeutic modalities such as hyperthermia (HT) [12][13][14][15] and chemotherapy. [16][17][18][19][20][21] Our previous study demonstrated that HT enhanced the absorbed dose with 131 I-A7 anti-colorectal cancer mAb to colon cancer xenografts and significantly improved the therapeutic efficacy of RIT.…”

Section: Abstract: Radioimmunotherapy -Local Hyperthermia -Chemothermentioning

confidence: 99%

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

Kinuya

Yokoyama

Konishi

et al. 2000

Japanese Journal of Cancer Research

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We previously found that the efficacy of radioimmunotherapy (RIT) with 131 I-A7, an IgG 1 against M r 45000 glycoprotein on colon cancer, was enhanced by local hyperthermia (HT) or chemotherapy with 5-fluorouracil (5-FU). In this study, we aimed to further enhance its efficacy by combining these three modalities. Human colon cancer xenografts (146 ± ± ± ±12 mm 3 ) in Balb/c nu/nu female mice were treated with 9.25 MBq Efficacy of radioimmunotherapy (RIT) has been examined in various kinds of malignant tumors.1-5) Its outcome, however, has been inadequate except for malignant lymphoma, 3,4) mainly because of limited delivery of radiation ranging around only 0.005-0.01% of the injected dose per gram of tumor. 6) Therefore, several kinds of strategies have been examined to improve its efficacy, including the use of biological response modifiers to increase tumor targeting of labeled monoclonal antibodies (mAbs), 7-9) the use of a pretargeting system to obtain a better therapeutic ratio to normal tissues 10,11) and combination with other therapeutic modalities such as hyperthermia (HT) [12][13][14][15] and chemotherapy. 16-21)Our previous study demonstrated that HT enhanced the absorbed dose with 131 I-A7 anti-colorectal cancer mAb to colon cancer xenografts and significantly improved the therapeutic efficacy of RIT.15) The combination of systemic chemotherapy with 5-fluorouracil (5-FU) also enhanced efficacy in the same model. 21) In addition, these studies showed that local HT did not affect myelotoxicity of RIT, and 131 I-A7 and 5-FU were able to be combined at near maximum tolerated doses (MTD) with only a slight increase of myelotoxicity. Intestinal toxicity of 5-FU would not be increased by 131 I-A7 either, as indicated by dosimetric analysis. 21) These findings suggested that the combination of these three modalities would be feasible in terms of its toxicity and may produce better antitumor efficacy than the two-modality combination of RIT with either HT or 5-FU. Therefore, the aim of this study was to investigate if the three-modality combination would be of benefit for enhancing the antitumor efficacy in colon cancer xenografts. MATERIALS AND METHODSMonoclonal antibody and animal model A7, an IgG 1 murine mAb that recognizes M r 45000 tumor associated glycoprotein of colorectal cancer, 22) was a gift from former Professor Toshio Takahashi and Dr. Toshiharu Yamaguchi, First Department of Surgery, Kyoto Prefectural University of Medicine. The mAb was labeled with 131 I by the chloramine-T method and purified on a PD10 column (Pharmacia LKB Biotechnology, Uppsala, Sweden). To prevent autoradiolysis of 131 I-A7, 5 mg/ml of ascorbic acid was added as a radioprotectant.23) The specific activity of 131 I-A7 was 94.7-113.2 MBq/mg and its immunoreactivity was 72.1-77.8% at infinite antigen excess, determined

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“…An opinion shared by many is that radioconjugates may be best applied clinically in solid tumors if combined with a chemotherapeutic agent (Wong, 2006). Most combinations examined preclinically have sought to add a chemotherapeutic agent to enhance the effect of a full dose of the radioconjugate (DeNardo et al, 1997b;Crow et al, 2005;Kelly et al, 2006;Masters et al, 2006), whereas others seek to enhance an effective, yet not curative, chemotherapy regimen with a smaller dose of the radioconjugate (Cardillo et al, 2002;Gold et al, 2003) A few phase I clinical trials have examined the former approach in patients with advanced solid tumors. Some treatment regimens used myeloablative radioconjugate doses with the aid of bone marrow or peripheral stem cell support, but without evidence of objective responses (Wong et al, 2003;Forero et al, 2005;Richman et al, 2005;Sharkey et al, 2005b).…”

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confidence: 99%

Novel radiolabeled antibody conjugates

Goldenberg

Sharkey

2007

Oncogene

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This article reviews the development of radioimmunoconjugates as a new class of cancer therapeutics. Numerous conjugates involving different antigen targets, antibody forms, radionuclides and methods of radiochemistry have been studied in the half-century since radioactive antibodies were first used in model systems to selectively target radiation to tumors. Whereas directly conjugated antibodies, fragments and subfragments have shown promise preclinically, the same approaches have not gained success in patients except in radiosensitive hematological neoplasms, or in settings involving minimal or locoregional disease. The separation of tumor targeting from the delivery of the therapeutic radionuclide in a multistep process called pretargeting has the potential to overcome many of the limitations of conventional, or onestep, radioimmunotherapy, with initial preclinical and clinical data showing increased sensitivity, specificity and higher radiation doses delivered. Our particular focus in pretargeting is the use of bispecific, trimeric (three Fab 0 s) constructs made by a new antibody engineering method termed 'dock-and-lock.'

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Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

Abstract: Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol

Cited by 92 publications

References 25 publications

Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia

Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

Novel radiolabeled antibody conjugates

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