Reduced Oxygen Enhancement Ratio at Low Doses of Ionizing Radiation

Palcic, Branko; Skarsgard, L. D.

doi:10.2307/3576354

Cited by 167 publications

(66 citation statements)

References 23 publications

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“…How anaemia is causally related to poor outcome is not entirely clear but it is probably both a marker of advanced tumour and indicative of some degree of tissue hypoxia. Because it is an axiom in radiobiology that hypoxic cells are less radioresponsive than aerated cells (Gray et al, 1953;Palcic and Skarsgard, 1984), it has been standard treatment to transfuse anaemic cancer patients to some arbitrary haemoglobin level in an effort to improve tissue oxygenation as well as to enhance patient comfort (Poskitt, 1987). Despite this practice, the routine use of blood transfusion to improve serum haemoglobin level has risks, including viral infection (HIV and hepatitis) and transfusion reaction (Bove, 1987;Poskitt, 1987;Levine and Vijayakumar, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

Sweeney

Nicolae²,

Ignacio³

et al. 1998

Br J Cancer

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Summary The purpose of this study was to determine the safety, efficacy and impact on quality of life of recombinant human erythropoietin (r-HuEPO) for cancer patients undergoing radiotherapy (RT). An open-labelled randomized design was used, with patients randomized to either treatment or control arms. Patients in the treatment arm received r-HuEPO given by subcutaneous injection at a dose of 200 units kg-' day-' plus oral iron supplements (ferrous sulphate 325 mg p.o. t.i.d.). Entry was restricted to patients with carcinoma of the lung, uterine cervix, prostate or breast who presented for RT with anaemia parameters reflective of 'the anaemia of chronic disease'. Radiotherapy policies (portals, doses, fraction size, etc.) were determined by the site and stage of disease. Complete blood counts (CBCs) were obtained weekly. The target level of haemoglobin was 15 g dl-1 for men and 14 g dl-1 for women. Quality of life (QOL) was assessed weekly by using an analogue scale to judge energy, activities of daily living and overall quality of life. Forty-eight patients were entered in the study, 24 in the treatment arm and 24 in the control arm. The prerandomization demographic characteristics and mean laboratory values were comparable in both arms. The mean haemoglobin at completion was 13.6 g dl-1 for r-HuEPO-treated patients compared with 11.0 g dl-1 for control subjects (P= 0.0012). Patients who received r-HuEPO demonstrated a mean weekly haemoglobin increase of 0.41 g dl-1 compared with a decrease in mean haemoglobin level in controls for 6 of the 7 weeks of the study (mean weekly decrease of 0.073 g dl-'). Target levels of haemoglobin were achieved by 41.6% of r-HuEPO-treated patients compared with none of the control subjects. The mean platelet count declined in both arms of the study with RT but the decline from pretreatment was less rapid in r-HuEPO-treated patients (11.2% decrease) compared with controls (26.3% decrease) and was statistically significant during weeks 4-6. Toxicity was minor with only mild irritation at the injection site. Mean quality of life end points were superior in the treatment arm but not statistically significant. r-HuEPO had a beneficial effect on weekly haemoglobin levels in patients undergoing RT with response rates similar to other studies. There was also a less rapid decline in weekly platelet counts in r-HuEPO-treated patients compared with control subjects. Further studies are needed to address the optimum dose and scheduling as well as the impact of r-HuEPO on clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

Sweeney

Nicolae²,

Ignacio³

et al. 1998

Br J Cancer

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“…1]. The OER is calculated as the ratio of doses needed to achieve the same biological effect (cell death) under hypoxic and oxic conditions, and can be as high as 3.0 for most tissues (1,(19)(20)(21). The success of fractionated radiotherapy is, therefore, partially attributed to reoxygenation of hypoxic regions over multiple treatments.…”

Section: Models Of Hypoxia and Resistance To Radiotherapy And Chemothmentioning

confidence: 99%

“Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair

Chan

Bristow

2010

Clinical Cancer Research

102

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Hypoxia exists in every solid tumor and is associated with poor prognosis because of both local and systemic therapeutic resistance. Recent studies have focused on the interaction between tumor cell genetics and the dynamic state of oxygenation and metabolism. Hypoxia generates aggressive tumor cell phenotypes in part owing to ongoing genetic instability and a "mutator" phenotype. The latter may be due to suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and double-strand break (DSB) repair. We propose a theoretical model in which hypoxia-mediated defects in DNA repair can lead to "contextual loss of heterozygosity" and drive oncogenesis. Additionally, hypoxia-mediated repair defects can be specifically targeted by DNA damaging agents and/or "contextual synthetic lethality" to kill repair-deficient cells and preserve the therapeutic ratio. These proposed concepts support the interrogation of solid tumors to document repair defects in both oxic and hypoxic tumor subregions as a conduit to novel clinical trials within the context of personalized medicine. Clin Cancer Res; 16(18); 4553-60. ©2010 AACR.The microenvironment of solid tumors differs greatly from that of normal tissues as it can contain regions of hypoxia (a decreased level of oxygen), increased interstitial fluid pressure, and decreased pH and nutrient delivery (1, 2). Hypoxia is associated with both local and systemic therapy resistance, and decreased disease-free survival has been observed in many human cancers (3-11). Importantly, hypoxia is an adverse prognostic factor in cancers treated with either radiotherapy or surgery. Hence hypoxia is not only a determinant of local radio-or chemoresistance, but also tumor progression and systemic metastasis. The latter may be due to altered transcription and translation of metastatic genes, but could also be secondary to clonal selection of a "mutator" phenotype (12,13). This unstable phenotype may result from hypoxia-mediated suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and doublestrand break (DSB) repair [whether by homologous recombination (HR) or nonhomologous end-joining (NHEJ)]. Suppression of DNA repair in oxic and hypoxic cells may, therefore, have profound consequences, given that residual or misrepaired DNA breaks can be highly carcinogenic and generate chromosomal alterations in oncogenes and tumor suppressor genes during tumor progression (14,15).This report critically reviews preclinical and clinical studies that link tumor hypoxia and DNA repair pathways as drivers of genetic instability and tumor progression. We also highlight recent work in which these DNA repair defects in aggressive cancer cells can be exploited with novel therapeutic approaches. Models of Hypoxia and Resistance to Radiotherapy and ChemotherapyThe abnormal vasculature of tumors resulting from unregulated angiogenesis is probably the most important contributor to the development of both chronic and acute hypoxia in the majority of solid tumors (reviewed in ref. ...

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“…The aim of UFI combined with ACNU was to get a multiple effect by the combination of high fraction dose and ACNU (Mashiyama et al 1989). Low dose rate therapy has many biological benefits; its oxygen enhancement ratio (OER) is lower than that of conventional irradiation (Hall et al 1966 ;Palcic and Skarsgard 1984), it attacks more cells of the sensitive phase in the cell cycle (Mitchell et al 1979 ;Zeman and Bedford 1986) and reoxegenation occurs effectively during irradiation (Hill and Bush 1973 ;Kal and Barendsen 1972), and low dose rate teletherapy (LDRT) differs from brachytherapy in that it is useful for treating any kind of tumor (Pierquin et al 1987). We applied this LDRT as a boost because of the possibility that radioresponsibility of residual tumor cells after full dose of irradiation had been changed (Milas et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Treatment Results by Uneven Fractionated Irradiation, Low-Dose Rate Telecobalt Therapy as a Boost, and Intraoperative Irradiation for Malignant Glioma.

Yamada¹,

Takai²,

Nemoto³

et al. 1992

Tohoku J. Exp. Med.

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Reduced Oxygen Enhancement Ratio at Low Doses of Ionizing Radiation

Cited by 167 publications

References 23 publications

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

“Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair

Treatment Results by Uneven Fractionated Irradiation, Low-Dose Rate Telecobalt Therapy as a Boost, and Intraoperative Irradiation for Malignant Glioma.

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