Post-treatment skin reactions reported by cancer patients differ by race, not by treatment or expectations

Cancer patients may experience skin problems while undergoing chemotherapy and radiation therapy. Frequency of skin reactions may be influenced by skin pigmentation and psychological factors. A Symptom Inventory completed by 656 cancer patients nationwide before and after chemotherapy, radiation therapy, or chemotherapy plus radiation therapy was analysed to determine if treatment type, race (Black vs White), and pretreatment expectations influenced post-treatment skin reactions. Subsequent analysis of a local Symptom Inventory completed weekly for 5 weeks by 308 patients receiving radiation therapy examined severity of reported skin reactions. Significantly more patients receiving radiation therapy had stronger expectations of skin problems (62%) than patients receiving chemotherapy (40%, P=0.001) or chemotherapy plus radiation therapy (45%, P=0.003). Overall, expectations did not correlate with patient reported post-treatment skin problems in white (r=0.014, P=0.781) or black (r=0.021, P=0.936) patients. Although no significant difference was found between black and white patients in their pretreatment expectations of skin problems (P=0.32), black patients (10 out of 18, 56%) reported more skin problems than white patients (90 out of 393, 23%, P=0.001). Similarly, the local study showed that significantly more black patients (1 out of 5, 20%) reported severe skin reactions at the treatment site than white patients (12 out of 161, 8%). A direct correlation was observed between severity of skin problems and pain at the treatment site (r=0.541, P<0.001). Total radiation exposure did not significantly correlate with the report of skin problems at the treatment site for white or black patients. Overall, black patients reported more severe post-treatment skin problems than white patients. Our results suggest that symptom management for post-treatment skin reactions in cancer patients receiving radiation treatment could differ depending on their racial background

Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation

Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Δ-mtDNA4977), takes place. The Δ-mtDNA4977 has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Δ-mtDNA4977 was assessed by polymerase chain reaction (PCR). Significant levels of Δ-mtDNA4977 accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation. © 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.Alsbeih G, 2003, RADIOTHER ONCOL, V66, P341, DOI 10.1016-S0167-8140(02)00327-4; AMES BN, 1989, MUTAT RES, V214, P41, DOI 10.1016-0027-5107(89)90196-6; AMES BN, 1989, FREE RADICAL RES COM, V7, P121, DOI 10.3109-10715768909087933; ATTARDI G, 1988, ANNU REV CELL BIOL, V4, P289, DOI 10.1146-annurev.cb.04.110188.001445; Becker-Catania SG, 2000, MOL GENET METAB, V70, P122, DOI 10.1006-mgme.2000.2998; CORTOPASSI GA, 1992, P NATL ACAD SCI USA, V89, P7370, DOI 10.1073-pnas.89.16.7370; CORTOPASSI GA, 1990, NUCLEIC ACIDS RES, V18, P6927, DOI 10.1093-nar-18.23.6927; FRAGA CG, 1990, P NATL ACAD SCI USA, V87, P4533, DOI 10.1073-pnas.87.12.4533; GEARA FB, 1992, INT J RADIAT ONCOL, V24, P287; GEARA FB, 1993, INT J RADIAT ONCOL, V27, P1173; Gerhard GS, 2002, MECH AGEING DEV, V123, P155, DOI 10.1016-S0047-6374(01)00328-1; Jessie BC, 2001, EXP GERONTOL, V37, P169, DOI 10.1016-S0531-5565(01)00153-X; Khanna KK, 2001, NAT GENET, V27, P247, DOI 10.1038-85798; Kubota N, 1997, RADIAT RES, V148, P395, DOI 10.2307-3579525; Lee HC, 2001, MUTAT RES-GEN TOX EN, V493, P67, DOI 10.1016-S1383-5718(01)00160-7; LEE HC, 1994, BBA-MOL BASIS DIS, V1226, P37, DOI 10.1016-0925-4439(94)90056-6; Richard SM, 2000, CANCER RES, V60, P4231; SCHON EA, 1989, SCIENCE, V244, P346, DOI 10.1126-science.2711184; SHOFFNER JM, 1989, P NATL ACAD SCI USA, V86, P7952, DOI 10.1073-pnas.86.20.7952; SMEETS MFMA, 1993, INT J RADIAT BIOL, V63, P703, DOI 10.1080-09553009314552101; TAYLOR AMR, 1975, NATURE, V258, P427, DOI 10.1038-258427a0; Tchirkov A, 1997, HUM GENET, V101, P312, DOI 10.1007-s004390050634; WALLACE DC, 1992, ANNU REV BIOCHEM, V61, P1175, DOI 10.1146-annurev.bi.61.070192.005523; WALLACE DC, 1995, AM J HUM GENET, V57, P201; WALLACE DC, 1992, SCIENCE, V256, P628, DOI 10.1126-science.1533953; WALLACE DC, 1994, P NATL ACAD SCI USA, V91, P8739, DOI 10.1073-pnas.91.19.8739; WURM R, 1994, INT J RADIAT ONCOL, V30, P625; YEN TC, 1991, BIOCHEM BIOPH RES CO, V178, P124, DOI 10.1016-0006-291X(91)91788-E; YONEDA M, 1995, BIOCHEM BIOPH RES CO, V209, P723, DOI 10.1006-bbrc.1995.155965786

Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks

Nonhomologous end-joining (NHEJ) is the predominant pathway that repairs DNA double-strand breaks (DSBs) in mammalian cells. The DNA-dependent protein kinase (DNA-PK), consisting of Ku and DNA-PK catalytic subunit (DNA-PKcs), is activated by DNA in vitro and is required for NHEJ. We report that DNA-PKcs is autophosphorylated at Thr2609 in vivo in a Ku-dependent manner in response to ionizing radiation. Phosphorylated DNA-PKcs colocalizes with both γ-H2AX and 53BP1 after DNA damage. Mutation of Thr2609 to Ala leads to radiation sensitivity and impaired DSB rejoining. These findings establish that Ku-dependent phosphorylation of DNA-PKcs at Thr2609 is required for the repair of DSBs by NHEJ

Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation

AbstractPoint mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Δ-mtDNA4977), takes place. The Δ-mtDNA4977 has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Δ-mtDNA4977 was assessed by polymerase chain reaction (PCR). Significant levels of Δ-mtDNA4977 accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose–response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation

Protection from radiation-induced mitochondrial and genomic DNA damage by an extract of Hippophae rhamnoides.

Hippophae rhamnoides or seabuckthorn is used extensively in Indian and Tibetan traditional medicine for the treatment of circulatory disorders, ischemic heart disease, hepatic injury, and neoplasia. In the present study, we have evaluated the radioprotective potential of REC-1001, a fraction isolated from the berries of H. rhamnoides. Chemical analysis of the extract indicated that REC-1001 was *68% by weight polyphenols, and contained kaempferol, isorhamnetin, and quercetin. The effect of REC-1001 on modulating radiation-induced DNA damage was determined in murine thymocytes by measuring nonspecific nuclear DNA damage at the whole genome level using the alkaline halo assay and by measuring sequence/gene-specific DNA damage both in nuclear DNA (b-globin gene) and in mitochondrial DNA using a quantitative polymerase chain reaction. Treatment with 10 Gy resulted in a significant amount of DNA damage in the halo assay and reductions in the amplification of both the b-globin gene and mitochondrial DNA. REC-1001 dose-dependently reduced the amount of damage detected in each assay, with the maximum protective effects observed at the highest REC-1001 dose evaluated (250 lg/ml). Studies measuring the nicking of naked plasmid DNA further established the radioprotective effect of REC-1001. To elucidate possible mechanisms of action, the antioxidant properties and the free-radical scavenging activities of REC- 1001 were evaluated. REC-1001 dose-dependently scavenged radiation-induced hydroxyl radicals, chemically-generated superoxide anions, stabilized DPPH radicals, and reduced Fe3þ to Fe2þ. The results of the study indicate that the REC-1001 extract of H. rhamnoides protects mitochondrial and genomic DNA from radiation-induced damage. The polyphenols/ flavonoids present in the extract might be responsible for the free radical scavenging and DNA protection afforded by REC-1001. Environ. Mol. Mutagen. 47:647–656, 2006