Sensitivity of c‐erbB Positive Cells to a Ligand Toxin and Its Utility in Purging Breast Cancer Cells from Peripheral Blood Stem Cell (PBSC) Collections

Keir, Michelle; Fiddes, Rod; Biggs, J. C.; Kearney, Philip C.

doi:10.1634/stemcells.18-6-422

Cited by 9 publications

(7 citation statements)

References 23 publications

(26 reference statements)

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“…Non-viral-based purging systems In an ex vivo setting, several purging strategies such as, tumour targeting with monoclonal antibodies (MoAbs) and/or linked to toxins 39,40 positive haematopoietic stem AFP mRNA detected in all patients after 1st and 2nd rounds of (IC) but not detected in 3 4 samples after 3rd round of IC Kasahara et al cell (CD34 þ ) selection 41,42 ex vivo chemotherapy, 43 photodynamic purging processes 44,45 and receptor-targeted ligand toxins such as Shiga-like toxin-1, a ribosome-inactivating protein with receptor expression in several tumour cell lines but not in CD34 þ cells 46,47 have been tested to minimize tumour cell contamination in autografts and reduce post transplant relapse. While the efficacy of the latter two purging methods has yet to be tested in clinical trials, the other methods, for a number of reasons have not been universally adopted into the clinical setting for depleting autografts of tumour cells.…”

Section: Ex Vivo Purging Strategiesmentioning

confidence: 99%

Viral purging of haematological autografts: should we sneeze on the graft?

Thirukkumaran

Russell

Stewart

et al. 2007

Bone Marrow Transplant

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High-dose cytotoxic chemotherapy followed by autologous haematopoietic stem cell transplantation (ASCT) is extensively used for the treatment of many haematopoietic, as well as several epithelial cancers. Disease relapse may be the result of tumour contamination within autograft as evidenced by gene marking studies. The multiple purging strategies that have been described to date have not proven effective in most ASCT settings. This review addresses the possibility of using oncolytic viruses as a novel purging strategy. DNA viruses such as genetically engineered adenoviral vectors have widely been used to deliver either a prodrug-activating enzyme or express wild-type p53 selectively in tumour cells in ex vivo purging protocols. In addition, conditionally replicating adenoviruses that selectively replicate in tumour cells and herpes simplex virus type 1 are other DNA viruses that have been tested as ex vivo purging agents under laboratory conditions. Vesicular stomatitis virus (VSV) and reovirus are naturally occurring RNA viruses that appear to hold promise as purging agents under ex vivo and in vivo settings. Preclinical data demonstrate reovirus's purging potential against breast, monocytic and myeloma cell lines as well as patient-derived tumours of diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, Waldenstrom macroglobulinemia and small lymphocytic lymphoma. In addition, VSV has shown effective killing of leukaemic cell lines and multiple myeloma patient specimens. Given the increasing interest in the utilization of viruses as purging agents, the following review provides a timely summary of the potential and the challenges of oncolytic viruses as purging modalities during ASCT.

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Section: Ex Vivo Purging Strategiesmentioning

confidence: 99%

Viral purging of haematological autografts: should we sneeze on the graft?

Thirukkumaran

Russell

Stewart

et al. 2007

Bone Marrow Transplant

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“…Widely cited purging methods of autografts include the use of ex vivo chemotherapy, tumor targeting monoclonal antibodies linked with toxins or selected on immunocolumns, and positive (CD34 ϩ ) selection. 12,13 More recently, photodynamic purging processes, [14][15][16] virus-directed enzyme prodrug therapy, 17 receptor-targeted ligand toxins, 18,19 and attenuated replication-competent virus-based purging techniques 20 have been reported. Yet, to date no method has proved 100% successful in depleting autografts of tumor cells in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation

Thirukkumaran

Luider

Stewart

et al. 2003

Blood

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Hematologic stem cell rescue after highdose cytotoxic therapy is extensively used for the treatment of many hematopoietic and solid cancers. Gene marking studies suggest that occult tumor cells within the autograft may contribute to clinical relapse. To date purging of autografts contaminated with cancer cells has been unsuccessful. The selective oncolytic property of reovirus against myriad malignant histologies in in vitro, in vivo, and ex vivo systems has been previously demonstrated. In the present study we have shown that reovirus can successfully purge cancer cells within autografts. IntroductionAutologous hematopoietic progenitor stem cell (ASC) transplantations following high-dose chemotherapy has gained extensive application as a therapeutic modality in several malignancies. [1][2][3][4][5][6][7] Globally, the number of autologous blood and marrow transplantations now surpasses the number of allotransplantations. [6][7][8] Despite the significant increase in ASC transplantations, controversy still exists as to the contribution of minimal residual disease to the development of relapse after high-dose chemotherapy. Evidence supported by gene marking studies indicates relapse following high-dose ablative therapy followed by ASC transplantation may be due to contaminating cancer cells within the autograft. [9][10][11] It has been estimated that more than 30% of all autografts are contaminated with tumor cells, and this number likely will increase with better detection methodology and increasing use of ASC transplantations in patients with advanced disease.To minimize the number of contaminating tumor cells, a variety of purging techniques to rid the graft of residual tumor cells have been used. The ideal purging technique should preferentially destroy contaminating tumor cells while preserving the number and function of the collected stem cells. Widely cited purging methods of autografts include the use of ex vivo chemotherapy, tumor targeting monoclonal antibodies linked with toxins or selected on immunocolumns, and positive (CD34 ϩ ) selection. 12,13 More recently, photodynamic purging processes, [14][15][16] virus-directed enzyme prodrug therapy, 17 receptor-targeted ligand toxins, 18,19 and attenuated replication-competent virus-based purging techniques 20 have been reported. Yet, to date no method has proved 100% successful in depleting autografts of tumor cells in the clinical setting. Although several studies have suggested that graft manipulation is of clinical benefit, 21-24 until purging techniques lead to a complete eradication of contaminating tumor cells, it will be unclear whether the recurrence of the disease is the result of the contaminating tumor cells or a reflection of a resistant in vivo malignancy or both. In the present study we investigated the use of an unattenuated oncolytic virus, reovirus, as the basis for a novel purging strategy for ASC transplantation.Reovirus is an ubiquitous double-stranded RNA virus that can be isolated from the upper respiratory and gastrointestinal tract...

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“…HRG is one of the factors that influence the response of the cells to E2. Overexpression of HRG in MCF-7 cells has been shown to confer E2 independence and antiestrogen resistance (Keir et al, 2000). Furthermore, experimental data in our laboratory have demonstrated that HRG can interfere in the negative crosstalk regulation between erbB2 and the estrogen receptor (ER) (Peles and Yarden, 1993;Alper et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity

et al. 2003

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Heregulin (HRG) is an activator of the erbB2-, erbB3-and erbB4-(erbB-2/3/4) signaling pathway. Transfection of full-length HRG cDNA into the estrogen (E2)-dependent cell line MCF-7 promoted an invasive E2-independent phenotype, as well as persistent activation of the erbB-2/3/4 receptors. Moreover, HRG expression in MCF-7 cells renders the cells sensitive to the topoisomerase II inhibitor doxorubicin (Doxo). In an attempt to dissociate the tumorigenic effect of HRG from the sensitizing effect to chemotherapy, we constructed a structural deletion mutant of HRG. Transfection of the deletion mutant of HRG described in this study (HRG/M) into MCF-7 cells resulted in the dissociation of the tumorpromoting activity of HRG from the sensitization to Doxo, that is, although the cells did not become more aggressive or E2-independent they became more sensitive to Doxo. HRG/M was unable to autophosphorylate the erbB receptors and did not affect the level of MAPK phosphorylation. Furthermore, the intracellular localization of the protein was different from that of the fulllength protein. Our data show that the HRG/M sequences are sufficient to sensitize MCF-7 cells to Doxo, and provide evidence that this sensitization is independent of erbB2 activation.

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Sensitivity of c‐erbB Positive Cells to a Ligand Toxin and Its Utility in Purging Breast Cancer Cells from Peripheral Blood Stem Cell (PBSC) Collections

Cited by 9 publications

References 23 publications

Viral purging of haematological autografts: should we sneeze on the graft?

Viral purging of haematological autografts: should we sneeze on the graft?

Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation

A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity

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