Transfer of Drug Resistance Genes into Hematopoietic Stem Cells for Marrow Protection

Bertino, Joseph R.

doi:10.1634/theoncologist.2008-0173

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…O 6 BG has been in clinical trials in a variety of cancers (brain, breast and melanoma), mainly to increase the efficacy of anticancer alkylating agents such as temozolomide and BCNU; in these cases, it is well established that specific inhibition of MGMT by O 6 BG results in increased number of DNA crosslinks and, in turn, an enhanced alkylator efficacy. We are aware that myelosuppression is a major limitation in the clinical trials involving O 6 BG with alkylating agents, and this problem can be overcome by gene therapy efforts of transducing O 6 BG-resistant mutant MGMT into the hematopoietic stem cells, thus affording selective protection to hematopoietic stem cells (36,37). Recent studies have also shown that O 6 BG can increase the efficacy of cisplatin, cyclophosphamide, and nonalkylators like camptothecin, but the mechanisms involved are currently unclear.…”

Section: Discussionmentioning

confidence: 99%

Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis

Konduri

Ticku

Bobustuc

et al. 2009

Clinical Cancer Research

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Purpose: We sought to determine whether administration of a MGMT blocker, O 6 -benzyl guanine (O 6 BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth. Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O 6 BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated. Results: O 6 BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O 6 BG. In sharp contrast, protein expression and mRNA message of p21 cip1 were significantly increased. Interestingly, O 6 BG increases p53-mediated p21 cip1 transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21 cip1 and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O 6 BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O 6 BG inhibited expression of MGMT and cyclins, and increased expression of p21 cip1 . Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis. Conclusions: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O 6 BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. (Clin Cancer Res 2009;15(19):6087-95)

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Section: Discussionmentioning

confidence: 99%

Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis

Konduri

Ticku

Bobustuc

et al. 2009

Clinical Cancer Research

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“…There are no clinical data yet to suggest that MDR can be completely reversed using this RNA interference (RNAi) technology, but it is likely that drugs related to RNAi will be developed in the near future. (iv) Transferring MDR genes into NSCs, especially bone marrow stem cells (133)(134)(135). Most chemotherapeutic drugs suppress the bone marrow and, as a result, blood cells such as erythrocytes, leukocytes, and thrombocytes do not function properly, and the ensuing loss of oxygen transport, immune response, and bleeding control functions causes serious adverse effects.…”

Section: Future Perspectivesmentioning

confidence: 99%

Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance

Cho

Kim

2020

Front. Oncol.

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Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to various defensive mechanisms in cancer. Initially, overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) was considered the most important mechanism for drug resistance; hence, many investigators for a long time focused on the development of specific ABC transporter inhibitors. However, to date their efforts have failed to develop a clinically applicable drug, leaving only a number of problems. The concept of cancer stem cells (CSCs) has provided new directions for both cancer and MDR research. MDR is known to be one of the most important features of CSCs and thus plays a crucial role in cancer recurrence and exacerbation. Therefore, in recent years, research targeting CSCs has been increasing rapidly in search of an effective cancer treatment. Here, we review the drugs that have been studied and developed to overcome MDR and CSCs, and discuss the limitations and future perspectives.

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Modelling Control of Pore Number and Radii Distribution in Single-Cell Electroporation

Talele

Gaynor

2010

Technological Developments in Networking, Education and Automation

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Transfer of Drug Resistance Genes into Hematopoietic Stem Cells for Marrow Protection

Abstract: The study investigates the use of gene transfer with genes that confer drug resistance for the purpose of bone marrow protection from chemotherapy.

Cited by 3 publications

References 39 publications

Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis

Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis

Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance

Modelling Control of Pore Number and Radii Distribution in Single-Cell Electroporation

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