cancer-research

Daniels-Wells TR, Helguera G, Rodriguez JA, Leoh LS, Erb MA, Diamante G, Casero D, Pellegrini M, Martinez-Maza O, Penichet ML (2013) Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1. Toxicol In Vitro 27(1):220-231. doi: 10.1016/j.tiv.2012.10.006

Summary: The antibody-avidin fusion protein ch128.1Av has been shown to target the human transferrin receptor 1 (TfR1) and kill malignant B cells by blocking the use of iron. Combination of this construct with a mono-biotinylated saporin custom conjugate produces an iron-independent toxicity to TfR1-expressing cells, even those that are resistant to ch128.1Av alone. The saporin-containing conjugate induces a transcriptional response consistent with oxidative stress and DNA damage. The data also show that the saporin conjugate is not toxic to human hematopoeietic stem cells.

Usage: An antibody-avidin fusion protein (ch128.1Av) was mixed with MonoBiotin-ZAP to make an immunotoxin that targets the human transferrin receptor 1 (TfR1).

Related Products: MonoBiotin-ZAP (Cat. #BT-ZAP), Custom Conjugates

Ye Y, Viet CT, Dang D, Schmidt BL (2012) IB4 (+) neurons contribute to force-induced cancer pain but not cancer proliferation. Neuroscience 2012 Abstracts 67.10. Society for Neuroscience, New Orleans, LA.

Summary: The primary treatment for cancer pain is μ-opiates; however, often μ-opiates are not effective and they produce multiple debilitating side effects. Recent studies show that μ- and δ-opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which mediate thermal and mechanical pain, respectively. We investigated the contribution of IB4 (+) and IB4 (-) neurons to cancer-induced mechanical and thermal hypersensitivity and investigated the role of these fibers to cancer proliferation. We used two separate mouse cancer pain models: 1) a cancer supernatant injection model, and 2) an orthotopic cancer model. The former model isolated the effect of the cancer secretome while the latter examined the effect of the following constituents within the cancer microenvironment: the cancer, the cancer secretome and the host tissue. Using the cancer supernatant model, along with injection of a selective δ-opioid receptor agonist and a P2X3 antagonist to target IB4 (+) neurons, we showed that IB4 (+) neurons played arole in cancer-supernatant-induced mechanical allodynia, but not thermal hyperalgesia. Selective ablation of IB4 (+) neurons in the spinal cord using IB4-saporin affected cancer-supernatant-induced mechanical but not thermal hypersensitivity. In the orthotopic cancer model, mice with paw cancer exhibited both mechanical and thermal hypersensitivity. Selective ablation of IB4(+) neurons decreased mechanical hypersensitivity; however thermal hypersensitivity was increased. We hypothesized that increased thermal hyperalgesia was associated with a compensatory elevation of TRPV1 expression in the spinal cord. Thermal latency in the mouse cancer paw was increased by intrathecal TRPV1 antagonist and selective removal of TRPV1 terminals by capsaicin in the IB4-saporin treated mice compared to saporin treated mice. Mechanical threshold was not affected by either the TRPV1 antagonist or capsaicin treatment. In the spinal cord, TRPV1 protein levels were increased in cancer mice compared to naïve mice, and TRPV1 was likely to be increased in the IB4-saporin treated cancer mice compared to saporin treated cancer mice. We investigated cancer proliferation by measuring tumor volume. Tumor volume was not affected by selective ablation of IB4 (+) neurons. Our findings suggest that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X3 antagonist, might be effective for treating cancer pain in patients. Acknowledgements: Supported by NIH/NIDCR R21 DE018561

Related Products: IB4-SAP (Cat. #IT-10)

Berstad MB, Weyergang A, Berg K (2012) Photochemical internalization (PCI) of HER2-targeted toxins: Synergy is dependent on the treatment sequence. Biochim Biophys Acta 1820(12):1849-1858. doi: 10.1016/j.bbagen.2012.08.027

Summary: A majority of patients develop acquired resistance to trastuzumab, the monoclonal antibody recognizing HER2, coupled to a toxin as a breast cancer therapeutic. One of the modes of resistance is that the therapeutic molecule is trapped inside an endocytic vesicle. PCI is a technique that facilitates cytosolic release of molecules in vesicles. The authors investigated the potency of biotinylated trastuzumab combined with streptavidin-ZAP (Cat. #IT-27) on several cell lines.

Related Products: Streptavidin-ZAP (Cat. #IT-27)

Ye Y, Dang D, Viet CT, Dolan JC, Schmidt BL (2012) Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity. J Pain 13(6):524-531. doi: 10.1016/j.jpain.2012.01.006

Summary: DOR (δ opioid receptor) agonists produce minimal side effects and do not lead to tolerance, making them potential alternatives to the widely used μ opioid receptor agonists. Utilizing the fact that DOR’s are expressed by IB4-positive neurons, the authors injected the subarachnoid space between the L4 and L5 vertebrae of rats with 2.4 μg of IB4-SAP (Cat. #IT-10). 3 μg of saporin (Cat. #PR-01) was used as a control. The results indicate that pharmacological agents targeting IB4-positive neurons may have use in cancer pain treatment.

Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)

Selbo PK, Weyergang A, Eng MS, Bostad M, Maelandsmo GM, Hogset A, Berg K (2012) Strongly amphiphilic photosensitizers are not substrates of the cancer stem cell marker ABCG2 and provides specific and efficient light-triggered drug delivery of an EGFR-targeted cytotoxic drug. J Control Release 159(2):197-203. doi: 10.1016/j.jconrel.2012.02.003

Summary: Many anti-cancer drugs are substrates of the ATP-binding cassette transporter ABCG2. Unfortunately ABCG2 is also thought to play an important role in multi-drug resistance and the protection of cancer stem cells against chemotherapeutics and photodynamic therapy. This paper examined whether photosensitizers used in photochemical internalization (PCI) are substrates for ABCG2. Streptavidin-ZAP (Cat. #IT-27) was combined with biotinylated EGF and applied to cells in culture; saporin (Cat. #PR-01) was used as a control. The data show that PCI with the EGF-saporin toxin did not utilize ABCG2 to enter cells.

Related Products: Streptavidin-ZAP (Cat. #IT-27), Saporin (Cat. #PR-01)

Mitra N, Banda K, Altheide TK, Schaffer L, Johnson-Pais TL, Beuten J, Leach RJ, Angata T, Varki N, Varki A (2011) SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. J Biol Chem 286(26):23003-23011. doi: 10.1074/jbc.M111.244152

Summary: Siglec 12 (sialic acid-binding immunoglobulin-like lectin 12) is a sugar molecule that has mutated in humans to be inactive, but is active in other primates. The human version is found on some macrophages, various epithelial cell surfaces, and some human carcinoma cell lines. Using Mab-ZAP (Cat. #IT-04) and monoclonal antibodies against Siglec 12, the researchers demonstrated binding and internalization in a prostate cancer cell line, indicating that Siglec 12 may be a target for some cancer therapies.

Related Products: Mab-ZAP (Cat. #IT-04)

Polito L, Bortolotti M, Pedrazzi M, Bolognesi A (2011) Immunotoxins and other conjugates containing saporin-s6 for cancer therapy. Toxins (Basel) 3(6):697-720. doi: 10.3390/toxins3060697 PMID: 22069735

Ancheta LR, Lappi DA (2011) Basigin-2 (EMMPRIN), a prognostic marker, is a dynamic portal of entry into cancer cells. Cancer Res 71(8):5218. Proceedings of the American Association for Cancer Research Annual Meeting, Orlando, FL. doi: 10.1158/1538-7445.AM2011-5218

Related Products: Anti-Basigin2-SAP (Cat. #IT-54)

Read the featured article in Targeting Trends.

Sawada R, Sun SM, Wu X, Hong F, Ragupathi G, Livingston PO, Scholz WW (2011) Human monoclonal antibodies to Sialyl-Lewisa (CA19.9) with potent CDC, ADCC, and antitumor activity. Clin Cancer Res 17(5):1024-1032. doi: 10.1158/1078-0432.CCR-10-2640

Summary: In this work the authors investigated the use of a carbohydrate antigen, sialyl-Lewisa (CA19.9), as a target for cancer therapeutics. Human monoclonal antibodies were generated against CA19.9 and characterized using ELISA and flow cytometry. To assess internalization one antibody, 5B1, was combined with Hum-ZAP (Cat. #IT-22) and applied to CA19.9-expressing BxPC3 cells. The cytotoxicity of the 5B1-Hum- ZAP complex indicates that CA19.9 may be a target for cancer therapy.

Related Products: Hum-ZAP (Cat. #IT-22)

Quadros EV, Nakayama Y, Sequeira JM (2010) Targeted delivery of saporin toxin by monoclonal antibody to the transcobalamin receptor, TCblR/CD320. Mol Cancer Ther 9(11):3033-3040. doi: 10.1158/1535-7163.MCT-10-0513

Summary: Vitamin B12 is necessary for cell proliferation. Cancer cells display an increased expression of TCb1R, the receptor that facilitates the intake of B12. In order to evaluate the potential of using immunotoxins to eliminate cancer cells expressing TCb1R the authors performed a series of in vitro experiments using their monoclonal antibodies plus Mab-ZAP (Cat. #IT-04). The results indicate that this is a viable therapeutic model that causes minimal peripheral damage.

Related Products: Mab-ZAP (Cat. #IT-04)