Assessing tumors in living animals through measurement of urinary β-human chorionic gonadotropin

Shih, Ie Ming; Torrance, C; Sokoll, Lori J.; Chan, Daniel W.; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1038/76299

Cited by 33 publications

(30 citation statements)

References 18 publications

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“…To enable monitoring of tumor burden in this systemic model, we transduced the KAS 6/1 cells with a lentiviral vector to express the soluble b-chain of human chorionicgonadotropin (bhCG) so that total tumor burden can be quantitated by measuring plasma levels of bhCG . 28 As shown in Figure 4b, both virus and virusinfected cells were able to traffick to and spread the virus infection within the tumors. When we plotted total tumor burden (plasma bhCG levels) against viral gene expression (luciferase activity), we found a very good correlation between total tumor burden in the mice and virus gene expression (r 2 ¼ 0.92) with a significant P-value of o0.0001.…”

Section: Multimodality Imaging Of Delivery Of Mv-luc By T Cells To Sumentioning

confidence: 94%

“…KAS 6/1 cells were also transduced with a HIV-1-based lentiviral vector expressing the b-chain of human chorionicgonadotropin (bhCG) to generate KAS-bhCG to allow non-invasive monitoring of tumor growth in vivo through analysis of levels of soluble peptide in the blood of the animals. 28 Blood from healthy volunteers were collected in heparinized tubes, layered on Ficoll-Paque Plus (Amersham Biosciences, Uppsala, Sweden) and centrifuged at 800 g for 30 min. The buffy coat was isolated and maintained in serum-free T-cell expansion medium (Sigma, St Louis, MO, USA).…”

Section: Cell Culture and Virusesmentioning

confidence: 99%

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Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies

et al. 2006

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Section: Multimodality Imaging Of Delivery Of Mv-luc By T Cells To Sumentioning

confidence: 94%

Section: Cell Culture and Virusesmentioning

confidence: 99%

Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies

et al. 2006

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“…United Biotech, Inc., or from ALPHA DIAGNOSTIC INTERNATIONAL, as well as from Sunnybrook Hospital Biochemistry services. Urine h-hCG levels were normalized by concomitant measurement of urine creatinine levels (using QuantiChrom TM Creatinine assay kit from BioAssay Systems) as detailed by Shih et al (8). Urine was collected by placing mice in empty, aerated, tip boxes for 2 to 3 h. Typically, 0.1 to 0.4 mL of urine would be collected per mouse in this manner, of which (depending on the tumor burden) 1 to 50 AL would be used for h-hCG detection and, 4 AL would be used for Creatinine measurement.…”

Section: B-hcg Measurementsmentioning

confidence: 99%

“…The cDNA for the h-subunit of human chorionic gonadotropin (h-hCG) is transfected into tumor cell lines, which are then injected into recipient mice. Secreted h-hCG (9) is then measured in the urine as a surrogate marker of tumor growth, tumor burden, and response to therapy (8). Others and we successfully used this approach to detect relative primary or ascites tumor burden (8, 10, 11) but not for metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

“…The use of prostatespecific antigen levels in the blood of men with recurring prostate cancer and reductions of prostate-specific antigen levels after therapy are examples of this approach. In this regard, Shih et al (8) developed a method that permits a marker to be used in a similar fashion for any transplanted tumor. The cDNA for the h-subunit of human chorionic gonadotropin (h-hCG) is transfected into tumor cell lines, which are then injected into recipient mice.…”

Section: Introductionmentioning

confidence: 99%

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Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines

Francia

Emmenegger

Lee

et al. 2008

Molecular Cancer Therapeutics

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Historically, the use of mouse models of metastatic disease to evaluate anticancer therapies has been hampered because of difficulties in detection and quantification of such lesions without sacrificing the mice, which in turn may also be dictated by institutional or ethical guidelines. Advancements in imaging technologies have begun to change this situation. A new method to noninvasively measure tumor burden, as yet untested to monitor spontaneous metastases, is the use of transplanted tumors expressing secretable human B-chorionic gonadotropin (B-hCG) that can be measured in urine. We describe examples of B-hCG -transfected tumor cell lines for evaluating the effect of different therapies on metastatic disease, which in some cases involved monitoring tumor growth for >100 days. We used B-hCG -tagged mouse B16 melanoma and erbB-2/Her-2 -expressing human breast cancer MDA-MB-231 models, and drug treatments included metronomic low-dose cyclophosphamide chemotherapy with or without a vascular endothelial growth factor receptor 2 -targeting antibody (DC101) or trastuzumab, the erbB-2/Her-2 -targeting antibody. Both experimental and spontaneous metastasis models were studied; in the latter case, an increase in urine B-hCG always foreshadowed the development of lung, liver, brain, and kidney metastases. Metastatic disease was unresponsive to DC101 or trastuzumab monotherapy treatment, as assessed by B-hCG levels. Our results also suggest that B-hCG levels may be set as an end point for metastasis studies, circumventing guidelines, which have often hampered the use of advanced disease models. Collectively, our data indicates that B-hCG is an effective noninvasive preclinical marker for the long term monitoring of untreated or treated metastatic disease. [Mol Cancer Ther 2008;7(10):3452 -9]

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Mouse Models of Advanced Spontaneous Metastasis for Experimental Therapeutics

Parra¹,

Miramontes²,

Francia³

et al. 2016

Methods and Principles in Medicinal Chemistry

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An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. Limited value of mouse therapy models Preclinical tumour models are a fundamental component of the study and design of new regimens for cancer treatment. Nonetheless, there are considerable shortcomings in the models used, both past and present. To cite just a few examples, tumour cell lines implanted subcutaneously in mice generally tend to grow rapidly and thus do not mimic the much slower doubling times of most human cancers. This may render them, for example, much more sensitive to most chemotherapy drugs that target dividing cells. It is also unclear whether ectopic (out of the normal place) subcutaneously implanted tumours-still a standard methodology-will respond to a therapy in the same way if grown in an orthotopic site 1 (in their organ or tissue of origin, such as breast cancers in mammary fat pads). In addition, tumour-bearing mice are often treated with drugs at levels, or with pharmacokinetics, that are not relevant to humans 2-4. Furthermore, almost all the preclinical models that have been studied have not involved tumours that were pre-exposed to another therapy, whereas many Phase I and Phase II clinical trials involve patients who have already undergone and progressed under first, second, or even more therapies and to which their tumours have become refractory. In addition, these models fail to reflect Phase I, Phase II and most Phase III clinical trials of patients with advanced metastatic disease in multiple

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Assessing tumors in living animals through measurement of urinary β-human chorionic gonadotropin

Cited by 33 publications

References 18 publications

Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies

Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies

Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines

Mouse Models of Advanced Spontaneous Metastasis for Experimental Therapeutics

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