Extent of Damage and Repair in the p53 Tumor-Suppressor Gene After Treatment of Myeloma Patients With High-Dose Melphalan and Autologous Blood Stem-Cell Transplantation Is Individualized and May Predict Clinical Outcome

2005 ◽  
Vol 23 (19) ◽  
pp. 4381-4389 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Vassilis L. Souliotis ◽  
Athanasios Anagnostopoulos ◽  
Christos Papadimitriou ◽  
Petros P. Sfikakis
Keyword(s):  
Dna Damage ◽  
Autologous Blood ◽  
P53 Gene ◽  
Suppressor Gene ◽  
High Dose ◽  
Blood Leukocytes ◽  
P53 Tumor Suppressor Gene ◽  
The Individual ◽  
High Dose Melphalan

Purpose To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). Patients and Methods The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m2) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. Results The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). Conclusion Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure.

scholarly journals Chemical selectivity of nucleobase adduction relative to in vivo mutation sites on exon 7 fragment of p53 tumor suppressor gene

2015 ◽  
Vol 6 (10) ◽  
pp. 5554-5563 ◽  
Author(s):  
Spundana Malla ◽  
Karteek Kadimisetty ◽  
You-Jun Fu ◽  
Dharamainder Choudhary ◽  
Ingela Jansson ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
P53 Gene ◽  
Suppressor Gene ◽  
P53 Tumor Suppressor ◽  
P53 Tumor Suppressor Gene ◽  
Chemical Selectivity

A 32-bp fragment of P53 gene reacted with benzo[a]pyrene metabolite BPDE was analyzed by LC-MS/MS. Chemically reactive sites were similar to frequently mutated codons in tumors.

scholarly journals Biological and clinical importance of the p53 tumor suppressor gene

1996 ◽  
Vol 42 (6) ◽  
pp. 858-868 ◽  
Author(s):  
V E Velculescu ◽  
W S El-Deiry
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Chemotherapeutic Agents ◽  
Cellular Growth ◽  
P53 Tumor Suppressor ◽  
P53 Tumor Suppressor Gene ◽  
P53 Antibodies

Abstract The p53 tumor suppressor gene controls cellular growth after DNA damage through mechanisms involving growth arrest and apoptosis. Mutations that inactivate p53 occur commonly in virtually all human malignancies and can be detected by sequencing of the p53 gene, immunohistochemical staining of tumor tissue with anti-p53 antibodies, single-strand conformation polymorphisms, or other biological assays. Identification of p53 mutation in the germ line is diagnostic of the cancer-prone Li-Fraumeni syndrome. Alterations of the p53 gene result in defective cellular responses after DNA damage and predispose cells to dysregulated growth, tumor formation and progression, and potential resistance (of tumor cells) to certain chemotherapeutic agents or ionizing radiation. A variety of tumors involving mutant p53 have a worse prognosis than tumors of the same type containing no p53 mutations. New diagnostic and therapeutic strategies are evolving as the p53 pathways of cell-cycle arrest and apoptosis become elucidated.

scholarly journals A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2840
Author(s):  
Dana M. Zaher ◽  
Wafaa S. Ramadan ◽  
Raafat El-Awady ◽  
Hany A. Omar ◽  
Fatema Hersi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Mitochondrial Metabolism ◽  
High Dose ◽  
Anticancer Effect ◽  
Safety Margins ◽  
Wide Range

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

Study of p53 codon 72 polymorphism and codon 249 mutations in Southern India in relation to age, alcohol drinking and smoking habits

2009 ◽  
Vol 29 (6) ◽  
pp. 451-458 ◽  
Author(s):  
K. Pandima Devi ◽  
B. Sivamaruthi ◽  
PV Kiruthiga ◽  
S. Karutha Pandian
Keyword(s):  
Lung Cancer ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Allele Polymorphism ◽  
P53 Codon 72 ◽  
Codon 72 ◽  
Lung Cancers ◽  
The Status ◽  
Study Population ◽  
The Individual

Germline polymorphisms of genes involved in different steps of tumorigenesis like p53, the tumor suppressor gene, are reported to determine the individual susceptibility to cancer. Lung cancer is one of the most common and lethal cancers and tobacco smoking remains its most important etiologic factors. The most frequently p53 mutated codons of lung cancer are 72 (exon 4) and 249 (exon 7). Since mutations in the p53 gene are present in ∼40% of all human lung cancers and are more common in smokers than in nonsmokers, we aimed to detect the status of p53 at codon 72 for Arg/Arg or Arg/Pro or Pro/Pro allele polymorphism and p53 codon 249 mutation in smokers and nonsmokers of South India. Allele frequencies in the nonsmokers were 0.16 for the Arg/Pro allele and 0.84 for the Pro/Pro allele in our study population. Among the smokers, the frequencies of the Arg/Pro, Arg/Arg, and Pro/Pro alleles were 0.88, 0.04, and 0.08, respectively. No mutation was detected in both smokers and nonsmokers in p53 codon 249. From the worldwide scenario, it can be speculated that the smokers, with Arg/Pro genotype are more prone for lung cancer or to other types of cancer.

scholarly journals PML Colocalizes with and Stabilizes the DNA Damage Response Protein TopBP1

2003 ◽  
Vol 23 (12) ◽  
pp. 4247-4256 ◽  
Author(s):  
Zhi-Xiang Xu ◽  
Anna Timanova-Atanasova ◽  
Rui-Xun Zhao ◽  
Kun-Sang Chang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Growth Regulation ◽  
Suppressor Gene ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Multifunctional Protein ◽  
Damage Response

ABSTRACT The PML tumor suppressor gene is consistently disrupted by t(15;17) in patients with acute promyelocytic leukemia. Promyelocytic leukemia protein (PML) is a multifunctional protein that plays essential roles in cell growth regulation, apoptosis, transcriptional regulation, and genome stability. Our study here shows that PML colocalizes and associates in vivo with the DNA damage response protein TopBP1 in response to ionizing radiation (IR). Both PML and TopBP1 colocalized with the IR-induced bromodeoxyuridine single-stranded DNA foci. PML and TopBP1 also colocalized with Rad50, Brca1, ATM, Rad9, and BLM. IR and interferon (IFN) coinduce the expression levels of both TopBP1 and PML. In PML-deficient NB4 cells, TopBP1 was unable to form IR-induced foci. All-trans-retinoic acid induced reorganization of the PML nuclear body (NB) and reappearance of the IR-induced TopBP1 foci. Inhibition of PML expression by siRNA is associated with a significant decreased in TopBP1 expression. Furthermore, PML-deficient cells express a low level of TopBP1, and its expression cannot be induced by IR or IFN. Adenovirus-mediated overexpression of PML in PML−/− mouse embryo fibroblasts substantially increased TopBP1 expression, which colocalized with the PML NBs. These studies demonstrated a mechanism of PML-dependent expression of TopBP1. PML overexpression induced TopBP1 protein but not the mRNA expression. Pulse-chase labeling analysis demonstrated that PML overexpression stabilized the TopBP1 protein, suggesting that PML plays a role in regulating the stability of TopBP1 in response to IR. Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage.

Sign in / Sign up

Export Citation Format

Share Document