XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

Persaud, Avinash K.; Johnson, Jay; Seligson, Nathan D.; Sborov, Douglas W.; Duah, Ernest; Cho, Yu Kyoung; Wang, Daqing; Phelps, Mitch A.; Hofmeister, Craig C.; Poi, Ming

doi:10.1002/mc.23121

Cited by 9 publications

(10 citation statements)

References 48 publications

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“…SCC83-82, a precancerous oral cell line, was kindly provided by Dr. Christopher Weghorst at the College of Public Health, The Ohio State University (31). Cells were grown in advanced DMEM/F12 (Life Technologies Corporate), supplemented with 5% FBS, and 1×Antibiotic Antimycotic solution as previously described (32).…”

Section: Methodsmentioning

confidence: 99%

A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy

Persaud

Johnson

et al. 2021

Anticancer Res

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Background: It has been reported that expressionof OCT3 enhanced the sensitivity to melphalan in cells, indicative of potential roles of OCT3 in melphalan transport. Herein we investigated the association of select single nucleotide polymorphisms in SLC22A3 (gene encoding OCT3) with clinical outcomes in multiple myeloma (MM) patients with hematopoietic autologous stem cell transplants followed by high-dose melphalan therapy. Materials and Methods: Melphlan concentrations in blood samples from 108 MM patients were measured using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS); genotypes of rs2048327, rs1810126, and rs3088442 in these patients were determined using quatitive RT-PCR assays. Results: Rs3088442 A variantcarriers had a significantly increased risk of severe oral mucositis in comparison with homozygous rs3088442 G-carriers with adjusted odds ratio of 4.00 (95% CI=1. 25-14.7; p=0.027). Rs3088442 A carriers tended to have lower creatinine clearance (p=0.10) and higher maximum plasma concentration of melphalan (p=0.07). Conclusion: OCT3 might be involved in melphalan transport in MM patients.Multiple myeloma (MM) represents the 2 nd most common hematological malignancy characterized by a pattern of recurrent relapses and remains incurable due to resistance and relapse in almost all patients (1). Hematopoietic autologous stem cell transplant (HSCT) with high-dose intravenous melphalan (HDM) remains the "gold" standard of care and the most effective treatment for transplant-eligible patients (2-5). Notably, there are considerable variations among MM patients in regard to the efficacy of autoHSCT-HDM therapy and melphalan-induced side-effects. On one hand, about 20% of patients exhibit resistance to melphalan, as demonstrated by progression-free survival (PFS) much shorter than the PFS of the majority of MM patients, which is partially ascribed to inadequate dosing (6, 7). On the other hand, some patients suffered from severe adverse effects, such as oral mucositis, gastrointestinal toxicity, and infection, which arguably result from excessive dosing (8-12). Since the standard 200 mg/m 2 of melphalan is used in most MM patients (for some patients with severe renal dysfunction, 140 mg/m 2 ), the ability for melphalan to be metabolized in patients appears to be closely related to clinical outcomes (responses and adverse effects) (8,11). To date, it has been known that hydrolysis and renal 385 This article is freely accessible online. # Jasmine A. Johnson was an undergraduate student at the College of Pharmacy, The Ohio State University when this study was undertaken.

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Section: Methodsmentioning

confidence: 99%

A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy

Persaud

Johnson

et al. 2021

Anticancer Res

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“…Assays were performed in triplicate at least twice. Absolute IC 50 values (the concentration of cisplatin required to inhibit 50% of the cell viability) were determined using Kaleidagraph software (Synergy Software, Reading, PA, USA) as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

Cisplatin Induced the Expression of SEI1 (TRIP-Br1) Oncogene in Human Oral Squamous Cancer Cell Lines

VanGundy

Poi

2019

Anticancer Res

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Background/Aim: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. Materials and Methods: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. Results: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. Conclusion: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.

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“…Contraindicatory data from different studies have shown that genetic variants have been associated with the response of MM patients to high dose melphalan- based chemotherapy via single nucleotide polymorphisms (SNPs) in genes of the BER pathway [ 26 , 27 ]. Among these genes, XRCC1, a protein involved in BER and single-strand break repair, significantly resulted in the increase of accumulation of melphalan-induced DNA damage lesions in XRCC-1 –deficient myeloma cells and, in turn, sensitized them to melphalan treatment [ 28 ].…”

Section: Hdacs In Different Ddr Mechanismsmentioning

confidence: 99%

Targeting the Interplay between HDACs and DNA Damage Repair for Myeloma Therapy

Γκοτζαμανίδου

Terpou

Kentepozidis

et al. 2021

IJMS

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Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, and accounts for 10% of all hematologic malignancies and 1% of all cancers. MM is characterized by genomic instability which results from DNA damage with certain genomic rearrangements being prognostic factors for the disease and patients’ clinical response. Following genotoxic stress, the evolutionary conserved DNA damage response (DDR) is activated and, in turn, coordinates DNA repair with cell-cycle events. However, the process of carcinogenesis cannot be attributed only to the genetic alterations, but also involves epigenetic processes. Regulation of expression and activity of key players in DNA repair and checkpoint proteins are essential and mediated partly by posttranslational modifications (PTM), such as acetylation. Crosstalk between different PTMs is important for regulation of DNA repair pathways. Acetylation, which is mediated by acetyltransferases (HAT) and histone deacetylases (HDAC), not only affects gene expression through its modulation of histone tails but also has recently been implicated in regulating non-histone proteins. Currently, several HDAC inhibitors (HDACi) have been developed both in pre-clinical and clinical studies, with some of them exhibiting significant anti-MM activities. Due to reversibility of epigenetic changes during the evolutionary process of myeloma genesis, the potency of epigenetic therapies seems to be of great importance. The aim of the present paper is the summary of all data on the role of HDACi in DDR, the interference with each DNA repair mechanism and the therapeutic implications of HDACi in MM.

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XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

Cited by 9 publications

References 48 publications

A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy

A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy

Cisplatin Induced the Expression of SEI1 (TRIP-Br1) Oncogene in Human Oral Squamous Cancer Cell Lines

Targeting the Interplay between HDACs and DNA Damage Repair for Myeloma Therapy

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