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Purpose: RH1 is a newly developed bioreductive agent, and its bioactivation is mediated by the enzyme DT-diaphorase (DTD). We have shown previously that RH1 is highly cytotoxic against cells expressing high DTD, using the p53-mutated MDA231 human breast cancer cell line transfected with the DTD gene (D7 cells). We now report that both RH1 and gamma-irradiation cause D7 cells to arrest in the G2/M cell cycle phase and undergo polyploidy. The latter is a way of p53-mutated cells responding to DNA-damaging agents. Only a small proportion of the polyploid cells are clonogenic, hence polyploidy may contribute to the reproductive failure of the cells after RH1 and irradiation. Thus, we investigated the effect of RH1 and gamma-irradiation on the formation of polyploid cells and a sub-G1 population (as a measure of apoptosis) in relation to the G2/M cell cycle block.Methods and Materials: MDA231 D7 cells were treated using a range of RH1 doses. The cells were irradiated using 2 Gy or 5 Gy gamma-rays either as a single dose or in combination with RH1. An IC(90) dose (dose to kill 90% of the cells) of RH1 was administered for 3 h followed by irradiation after a further 24 h. Subsequent changes in cell cycle and polyploidy (DNA content in excess of that of G2/M cells) were examined.Results: Treatment of D7 cells with the RH1 resulted in 60-70% of cells arrested in the G2/M phase of the cell cycle by 24 h, which decreased to control levels by 48 h. Irradiation with 2 Gy and 5 Gy caused a similar G2/M block at 12-24 h, which was followed by a sharp decline at 24-48 h. In contrast, the same dose of radiation combined with RH1 held the cells in the G2/M phase up to 48 h, and this pattern reached pretreatment levels at 72-96 h. Most control cells were found to contain a small number of spontaneously arising polyploid cells. The development of polyploid cells was evident from 12 h after all treatments and showed a significant increase at 48 h and subsequently. As opposed to this, apoptosis measured by the sub-G1 cell population in DNA analyses showed a tendency to increase according to the elapsed time for each group of treatments. Single treatments with RH1 caused a significant increase in the apoptotic population between 48 and 120 h. The first significant increase in apoptosis was observed at 48 h for 5 Gy, 2 Gy + RH1, and 5 Gy + RH1 treatments, and showed a tendency to increase further at later times, but the 2 Gy dose gave an earlier apoptotic peak at 24 h, which decreased to 96 h. The addition of RH1 to the irradiation did not increase the formation of polyploid cells or apoptosis compared with radiation alone (2 Gy vs. RH1 + 2 Gy or 5 Gy vs. RH1 + 5 Gy). The higher dose of irradiation (5 Gy vs. 2 Gy) resulted in a significantly higher proportion of polyploid cells (but not of apoptotic cells) when used alone or in combination (5 Gy + RH1 vs. 2 Gy + RH1).Conclusions: Both RH1 and gamma-irradiation, individually and in combination, showed a significant G2/M block in MDA231 D7 breast cancer cells. The formation of polyploid cells was dependent more on the radiation dose rather than on the pretreatment with RH1. The polyploid cell population was observed after the G2/M cell cycle phase arrest, and it preceded the late increase of the apoptotic cell population. The role of polyploidy in cell reproductive failure in the total cell population is not known, but it appears to contribute to cytotoxicity in cells released from the G2/M cell cycle phase block. [ABSTRACT FROM AUTHOR]

Purpose: To compare the dose–volume histogram (DVH) parameters obtained by three-dimensional gynecologic brachytherapy planning with the rectosigmoid mucosal changes observed by flexible sigmoidoscopy. Methods and Materials: Between January 2004 and July 2005, 71 patients with International Federation of Gynecology and Obstetrics Stage IB–IIIB uterine cervical cancer underwent computed tomography-based high-dose-rate intracavitary brachytherapy. The total dose (external beam radiotherapy [RT] plus intracavitary brachytherapy) to the International Commission of Radiation Units and Measurements rectal point (ICRURP) and DVH parameters for rectosigmoid colon were calculated using the equivalent dose in 2-Gy fractions (α/β = 3 Gy). Sigmoidoscopy was performed every 6 months after RT, with the 6-scale scoring system used to determine mucosal changes. Results: The mean values of the DVH parameters and ICRURP were significantly greater in patients with a score of ≥2 than in those with a score <2 at 12 months after RT (ICRURP, 71 Gyα/β3 vs. 66 Gyα/β3, p = 0.02; D0.1cc, 93 Gyα/β3 vs. 85 Gyα/β3, p = 0.04; D1cc, 80 Gyα/β3 vs. 73 Gyα/β3, p = 0.02; D2cc, 75 Gyα/β3 vs. 69 Gyα/β3, p = 0.02). The probability of a score of ≥2 showed a significant relationship with the DVH parameters and ICRURP (ICRURP, p = 0.03; D0.1cc, p = 0.05; D1cc, p = 0.02; D2cc, p = 0.02). Conclusion: Our preliminary data have shown that DVH values of the rectosigmoid colon obtained by computed tomography-based three-dimensional brachytherapy planning are reliable and predictive of score ≥2 rectosigmoid mucosal changes. [Copyright &y& Elsevier]

Purpose: To quantify proton radiotherapy dose reduction in the prostate target volume because of the three-dimensional movement of the prostate based on an analysis of dose-volume histograms (DVHs). Methods and Materials: Twelve prostate cancer patients underwent scanning in supine position, and a target contour was delineated for each using a proton treatment planning system. To simulate target movement, the contour was displaced from 3 to 15 mm in 3-mm intervals in the superior-to-inferior (SI), inferior-to-superior (IS), anterior-to-posterior (AP), posterior-to-anterior (PA), and left-to-right (LR) directions. Results: For both intra- and interfractional movements, the average coverage index and conformity index of the target were reduced in all directions. For interfractional movements, the magnitude of dose reduction was greater in the LR direction than in the AP, PA, SI. and IS directions. Although the reduction of target dose was proportional to the magnitude of intrafractional movement in all directions, a proportionality between dose reduction and the magnitude of interfractional target movement was clear only in the LR direction. Like the coverage index and conformity index, the equivalent uniform dose and homogeneity index showed similar reductions for both types of target movements. Conclusions: Small target movements can significantly reduce target proton radiotherapy dose during treatment of prostate cancer patients. Attention should be given to interfractional target movement along the longitudinal direction, as image-guided radiotherapy may be ineffective if margins are not sufficient. [ABSTRACT FROM AUTHOR]

Purpose: To perform an intracavitary radiotherapy (ICR) plan comparison between the conventional point A plan (conventional plan) and computed tomography (CT)-guided clinical target volume-based plan (CTV plan) by analysis of the quantitative dose–volume parameters and irradiated volumes of organs at risk in patients with cervical cancer. Methods and Materials: Thirty plans for 192Ir high-dose-rate ICR after 30–40-Gy external beam radiotherapy were investigated. CT images were acquired at the first ICR session with artifact-free applicators in place. The gross tumor volume, clinical target volume (CTV), point A, and International Commission on Radiation Units and Measurements Report 38 rectal and bladder points were defined on reconstructed CT images. A fractional 100% dose was prescribed to point A in the conventional plan and to the outermost point to cover all CTVs in the CTV plan. The reference volume receiving 100% of the prescribed dose (Vref), and the dose–volume parameters of the coverage index, conformal index, and external volume index were calculated from the dose–volume histogram. The bladder, rectal point doses, and percentage of volumes receiving 50%, 80%, and 100% of the prescribed dose were also analyzed. Results: Conventional plans were performed, and patients were categorized on the basis of whether the 100% isodose line of point A prescription dose fully encompassed the CTV (Group 1, n = 20) or not (Group 2, n = 10). The mean gross tumor volume (11.6 cm3) and CTV (24.9 cm3) of Group 1 were smaller than the corresponding values (23.7 and 44.7 cm3, respectively) for Group 2 (p = 0.003). The mean Vref for all patients was 129.6 cm3 for the conventional plan and 97.0 cm3 for the CTV plan (p = 0.003). The mean Vref in Group 1 decreased markedly with the CTV plan (p < 0.001). For the conventional and CTV plans in all patients, the mean coverage index, conformal index, and external volume index were 0.98 and 1.0, 0.23 and 0.34, and 3.86 and 2.15, respectively. Statistical analysis showed that the conformal index and external volume index improved significantly with the CTV plan, and this improvement was more marked in Group 1. The mean values of the bladder and rectal point doses and volume fractions receiving 50%, 80%, and 100% of the reference dose did not differ between plans for all patients. The reduction in the mean rectal and bladder point doses and irradiated volumes for the CTV plan was statistically significant in Group 1. Conclusion: Computed tomography-guided CTV planning of ICR is superior to conventional point A planning in terms of conformity of target coverage and avoidance of overdosed normal tissue volume. To ascertain the potential benefit of treatment outcome, ICR with image-guided three-dimensional plans will be pursued and correlated with the dose–volume parameters. [Copyright &y& Elsevier]