Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

He, Chao; Li, Lun; Guan, Xuan; Li, Xiong; Miao, Xiangshui

doi:10.1159/000446361

Cited by 72 publications

(57 citation statements)

References 79 publications

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“…UWB1.289 + BRCA1 and UWB1.289 cells carry mutated TP53 tumor suppressor gene. TP53 mutations have an intricate role in the response to clinical chemjournalapy and are associated with short survival time and tumor resistance to radijournalapy and chemjournalapy in several tumors including resistance to classical and non‐classical alkylating agents . ENGA‐L06E and ENGA‐L08E demonstrated anticancer activity insusceptible to the presence of mutated TP53 while the alkylator PA was ineffective against UWB1.289 + BRCA1 cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells

et al. 2017

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Conjugated lactam-steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSA that generate excellent anticancer activity against UWB1.289 and UWB1.289 + BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289 + BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo, and in silico, experimental methods were utilized to determine the poly(ADP-ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects, and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSA. LSA produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1-mutated UWB1.289 ovarian cancer cells with defective PARP-oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells

et al. 2017

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“…Research into predictive biomarkers of response of EC treated with chemo(radio)therapy are in progress. P53 for predicting EC response has been reported . Li et al carried out a systematic review and meta‐analysis to summarize and evaluate the biomarkers for predicting response to chemo(radio)therapy.…”

Section: Multidisciplinary Therapymentioning

confidence: 99%

Recent advancements in esophageal cancer treatment in Japan

Tanaka

Yoshida

Suetsugu

et al. 2018

Annals of Gastroent Surgery

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The 11th edition of the Japanese Classification of Esophageal Cancer (EC) was published in 2017. Some correction was made in the depth of tumor invasion to be consistent with the TNM classification by the Union for International Cancer Control (UICC). With regard to surgery, short‐term safety and long‐term effectiveness under thoracotomy/video‐assisted thoracoscopic surgery are expected to be proven by the Japan Clinical Oncology Group (JCOG)1409 study. Results of nutritional management and countermeasures for adverse events not only during the perioperative period but also during EC chemotherapy were reported. From now on, the pursuit of low invasiveness and radicality is desired. Esophageal surgery is also expected to be safe at all institutions. To determine the optimal modality of preoperative treatment and a novel chemo(radio)therapy regimen for patients with distant metastasis, the results of the ongoing JCOG1109 and 0807 studies are being released. The effect of the addition of molecular targeted drugs on chemotherapy and concurrent chemoradiation has not yet improved overall survival. Immune checkpoint inhibitor drugs could offer a potential new treatment approach for patients with treatment‐refractory advanced squamous cell carcinoma (SCC). The Cancer Genome Atlas Research Network reported the results of a comprehensive genome analysis and molecular analysis of SCC and adenocarcinoma of the esophagus. Further differentiation of SCC and adenocarcinoma by molecular characterization analysis may be useful for the development of clinical trials and targeted drug therapies as precision medicine. The era of ultimate minimally invasive surgery and personalized treatment has begun. Large, prospective studies will be required to confirm the value of these advancements.

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“…Acute lymphoblastic leukemia (ALL) is a common hematological malignancy in children and adults, and treatment usually involves various anticancer drugs [1, 2]. High-dose methotrexate (HDMTX) is one of the most important agents in the treatment of extramedullary infiltration of ALL [3-5].…”

Section: Introductionmentioning

confidence: 99%

Identification of Risk Factors in High-Dose Methotrexate-Induced Acute Kidney Injury in Childhood Acute Lymphoblastic Leukemia

Cheng

Liu

et al. 2018

Chemotherapy

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Aims: Although high-dose methotrexate (HDMTX) is an effective means for the treatment of acute lymphoblastic leukemia (ALL), the development of renal dysfunction remains a significant management challenge. This study aimed to identify the key factors in HDMTX-induced acute kidney injury (AKI) in childhood ALL. Methods: We retrospectively analyzed the clinical data in 1,329 courses of HDMTX treatment in 336 Chinese ALL children at the First Affiliated Hospital of Guangxi Medical University from September 2012 to November 2016. The clinical data were compared between the groups of children with development of AKI and those without. Risk factors were identified by multiple logistic regression analysis, and the diagnostic performance of plasma MTX concentration was evaluated by receiver operating characteristic (ROC) curve analysis. Results: AKI was observed in 88 patients (26.2%) and 104 courses (7.8%). Binary logistic regression revealed that age (OR 1.349; p = 0.005), first HDMTX course (OR 1.767; p = 0.013), MTX dose per body surface area (BSA; OR 1.944; p = 0.015), and baseline serum total protein (OR 0.929; p = 0.021) significantly correlated with AKI. The area under the ROC for 48-h plasma MTX concentration was 0.890 (95% CI 0.850–0.930), and sensitivity and specificity values of the cut-off value were 78.8 and 90.4%, respectively. Conclusion: Increasing age, higher MTX dose per BSA, lower baseline serum protein, and first HDMTX course were significant risk factors for developing HDMTX-induced AKI in childhood ALL. The threshold of 48-h MTX plasma concentration is valuable for the prediction of HDMTX-induced AKI.

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Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Cited by 72 publications

References 79 publications

Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells

Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells

Recent advancements in esophageal cancer treatment in Japan

Identification of Risk Factors in High-Dose Methotrexate-Induced Acute Kidney Injury in Childhood Acute Lymphoblastic Leukemia

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