• Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: results of the ERISAC randomized placebo-controlled trial.

      Bundred, Nigel J; Cramer, Angela; Morris, Julie; Renshaw, Lorna; Cheung, Kwok-Leung; Flint, Pamela J; Johnson, Rachael; Young, Oliver; Landberg, Göran; Grassby, Sue; et al. (2010-03-01)
      PURPOSE: Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)-positive DCIS. Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 x 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision. RESULTS: Ninety women were randomized: all were ER positive, 49 (54%) had grade III tumors, and 29 (32%) were HER2 positive (3+). Exemestane reduced proliferation compared with placebo with a median reduction of 9% (95% confidence interval, 6-14; P < 0.001). Progesterone receptor was reduced by exemestane (mean decrease, 19%; 95% confidence interval, 9-28; P = 0.011). The effect of exemestane on proliferation was seen regardless of grade, HER2, or PR expression. Celecoxib had no effect on proliferation or apoptosis alone, or in combination with exemestane. CONCLUSIONS: Exemestane reduces proliferation in ER-positive DCIS. Aromatase inhibition is a potential alternative to tamoxifen in patients who have undergone breast conservation for ER-positive DCIS.
    • Cyclophosphamide and nandrolone decanoate in the treatment of advanced carcinoma of the breast--results of a comparative controlled trial of the agents used singly and in combination.

      Cole, M P; Todd, Ian D; Wilkinson, Peter M; Christie Hospital and Holt Radium Institute, Manchester (1973-05)
      A random trial in which cyclophosphamide, nandrolone decanoate and the two drugs in combination were used in the treatment of advanced breast carcinoma is described. The results suggest that it is preferable to use cyclophosphamide on its own.
    • Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation.

      Lee, Siow Ming; Crowther, Derek; Scarffe, J Howard; Dougal, Mark; Elder, Rhoderick H; Rafferty, Joseph A; Margison, Geoffrey P; CRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. (1992-08)
      O6-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m-2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 10 mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 microns acrolein or with greater than 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.
    • Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation.

      Czyz, A; Labopin, M; Giebel, S; Socié, G; Apperley, J; Volin, L; Reményi, P; Yakoub-Agha, I; Orchard, K; Michallet, M; et al. (2018-03-25)
      Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph-negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia-free survival (60% vs. 50%, P = .04), and improved "graft versus host disease (GVHD) and relapse-free survival" (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end-points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph-negative ALL treated with alloHCT.
    • Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas.

      Bramwell, Vivien H C; Mouridsen, H T; Santoro, A; Blackledge, G; Somers, R; Verwey, J; Dombernowsky, P; Onsrud, M; Thomas, D; Sylvester, R (1987-03)
      Ifosfamide (IFOS) 5 g/m2 and its parent analog Cyclophosphamide (CYCLO) 1.5 g/m2 were studied in a randomized phase II study, accruing 171 patients with advanced soft tissue sarcoma. Both drugs were administered as 24 hr infusions, every 3 weeks, with comcomitant Mesna 400 mg/m2 i.v. bolus 4 hourly X 9 doses. Twenty-four patients were ineligible and 12 were not evaluable. The groups were well matched for age, previous chemotherapy (42% of the total) or radiotherapy, the presence of distant metastases and performance status, but there were more females (59% vs. 45%) in the IFOS arm. Among the 68 evaluable patients receiving IFOS, there were 2 CR, 10 PR (overall response 18%), 27 SD and 29 PD. For CYCLO, the corresponding results in 67 patients were 1 CR, 4 PR (overall response 8%), 23 SD and 39 PD. Using the chi-square test the P values for response rate and linear trend were 0.13 and 0.04 respectively. Response rates were higher for females (20% vs. 5%, P = 0.01) and patients who had not received previous chemotherapy (19% vs. 4%, P = 0.01). Fourteen of the 17 responses came from a group of 43 females, who had not received previous chemotherapy, for whom the overall response rate was 37.5%. Remissions were noted in only 4 histological subtypes (centrally reviewed material), i.e., 5 of 17 synovial sarcomas, 7 of 13 mixed mesodermal sarcomas and 2 of 7 fibrosarcomas. One of the 31 leiomyosarcomas responded to Cyclophosphamide. Durations of response did not differ significantly between the 2 arms--median 26, range 10-81+ weeks. Leucopenia was significantly more severe on CYCLO, particularly in patients who had received previous chemotherapy (P = 0.007). Serious infections occurred in approx. 7% of patients with no difference between the two drugs, although there was one toxic death on CYCLO. Nausea and vomiting were significantly worse on IFOS and alopecia, related in extent to dose, was seen in both arms. Other side-effects, such as hematuria or rises in serum creatinine and encephalopathy, were infrequent and mild. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination therapy.
    • Cyclophosphamide versus ifosfamide: preliminary report of a randomized phase II trial in adult soft tissue sarcomas.

      Bramwell, Vivien H C; Mouridsen, H; Santoro, A; Blackledge, G; Somers, R; Thomas, D; Sylvester, R; Van Oosterom, A (1986)
      One hundred and seventy-one patients with advanced soft tissue sarcoma entered a randomized crossover phase II study comparing cyclophosphamide (CYCLO) with a new analogue, ifosfamide (IFOS), both administered as 24 h i.v. infusions every 3 weeks. The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2, with provision for dose escalation. All patients received mesna 400 mg/m2 as an i.v. bolus 4 hourly X 9 doses, commencing at the start of the oxazophosphorine infusion. Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent. There were 22 patients who were ineligible, and response could not be evaluated in 12 additional patients. IFOS produced two complete and ten partial remissions, for an overall response rate of 18%. CYCLO was significantly (P = 0.04) less active, producing one complete and five partial remissions, an overall response rate of 9%. Stabilization of disease was similar in both arms (27% and 24% respectively), but fewer patients showed progression on IFOS. The response rate was higher (20% vs 5%) for patients who had not received previous chemotherapy, and also for female compared with male patients (21% vs 5%). When only patients who had not received previous chemotherapy were considered, the respective response rates for IFOS and CYCLO were 24% and 15%. There were no responses in previously treated patients receiving CYCLO. There were four partial responses in 33 patients crossing from CYCLO to IFOS, but no responses in 18 patients receiving CYCLO after IFOS. Leucopenia was significantly more pronounced (P = 0.0004) with CYCLO, both after the first course and throughout treatment, although the incidence of severe infections, 6%, was the same in both arms. Nausea and vomiting were more severe with IFOS (P = 0.022), but other toxicities were mild. Grade 1 or 2 bladder (haematuria) or renal (rise in serum creatinine) toxicity was slightly more frequent with IFOS (7 vs 3 patients) and was a reason for stopping treatment for one patient in each arm. Three episodes of mild to moderate drowsiness after IFOS were reported, but no severe encephalopathy. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin.
    • Cyclosporin associated demyelination following allogeneic bone marrow transplantation.

      Lind, Michael J; McWilliam, L J; Jip, J; Scarffe, J Howard; Morgenstern, Godfrey R; Chang, James; CRC Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, U.K. (1989)
      Neurological complications associated with cyclosporin administration are well documented. However their histopathological basis are ill-understood. We describe below a case of demyelination following cyclosporin administration to a patient following allogeneic bone marrow transplantation.
    • CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

      Province, M; Goetz, M; Brauch, H; Flockhart, D; Hebert, J; Whaley, R; Suman, V; Schroth, W; Winter, S; Zembutsu, H; et al. (2014-02)
      The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
    • CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

      Johnson, N.; Maguire, S.; Morra, A.; Kapoor, P. M.; Tomczyk, K.; Jones, M. E.; Schoemaker, M. J.; Gilham, C.; Bolla, M. K.; Wang, Q.; et al. (2021)
      Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).
    • CYTOFLOC: Evaluation of a non-endoscopic immunocytological device (Cytosponge (TM)) for post-chemoradiotherapy surveillance in patients with oesophageal cancer - a feasibility study

      Mukherjee, S.; O'Connor, H.; Harman, R.; O'Donovan, M.; Debiram-Beecham, I.; Alias, B.; Bailey, A.; Bateman, A.; de Caestecker, J.; Crosby, T.; et al. (2021)
      Background: Accurate response assessment in patients with oesophageal cancer undergoing neo-adjuvant chemoradiotherapy would pave the way for more tailored management. Cytosponge TM consists of an expandable, spherical mesh attached to a string and contained within a soluble capsule. The capsule dissolves in the stomach, releasing the sponge which is retrieved by pulling the string. Oesophageal cells collected can be evaluated for molecular markers. CYTOFLOC evaluated feasibility, safety, acceptability and indicative accuracy of Cytosponge TM to assess response in patients with oesophageal cancer treated with definitive or neoadjuvant chemo radiotherapy (dCRT/nCRT). Methods: Inclusion: patients 16 years who have undergone dCRT/nCRT, 4-16 weeks post treatment, dysphagia score 0-2, able to swallow tablets and fit for endoscopy. Exclusion: varices, strictures, stent. Nurses were trained to administer the Cytosponge TM. Cytosponge TM was administered after 6 hours fast. Only 2 attempts at swallowing were provided. Acceptance was evaluated through patient questionnaires. Blood for ctDNA, and corresponding endoscopic/surgical histology assessment was optional. Primary Objective: Completion rate (The proportion of consented, evaluable, patients successfully undergoing Cytosponge TM). Secondary Objectives: Safety (all serious adverse events); Suitability of sample for biomarker analysis (Presence of cytological atypia and/or p53 mutation was considered +ve test); Acceptance rate (Proportion of eligible patients approached who consented; proportion of patients who would accept the procedure repeatedly). Tertiary Objectives: detection of ctDNA; Comparative efficacy of Cytosponge TM to resected/endoscopic histology. Results: 41 patients were recruited between April 2018 and January 2020 from 11 hospitals. Participant/tumour characteristics: Mean (SD) age 68.32 (10.3) years, median (IQR) baseline tumour length 5cm (2,7). Male:Female (33:8), Dysphagia grade 0:1:2(27:12:2), dCRT:nCRT (28:13), SCC:Adeno (25:16); Site upper:mid:lower:GO Junction (7:8:22:4). Overall completion rate was 39/41(95.1%, 95% CI 83.5-99.4). 41/ 96 (42.7%, 95% CI 32.7,53.2) eligible patients consented, and 37/39 (94.9%, 95% CI 82.7,99.4) were willing to accept repeated procedures. Three grade 1 AE were recorded (sore throat dysphagia, dyspepsia). 38/39 (97.4%, 95% CI 86.5,99.9) were considered suitable for biomarker analysis. 9/38 (24%) were considered positive by cytological criteria. Corresponding histology was available in 33 patients (3 positive on histology, 30 negative on histology). There was high-level agreement between negative samples. Of patients with negative histology, 4 patients were atypia positive/ uncertain on Cytosponge TM and 3 were p53 aberrant on Cytosponge TM.
    • Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator.

      Martinez-Outschoorn, U E; Whitaker-Menezes, D; Lin, Z; Flomenberg, N; Howell, Anthony; Pestell, R G; Lisanti, M P; Sotgia, F; Thomas Jefferson University, Philadelphia, PA, USA. (2011-06-01)
      Recently, we proposed a new paradigm for understanding the role of the tumor microenvironment in breast cancer onset and progression. In this model, cancer cells induce oxidative stress in adjacent fibroblasts. This, in turn, results in the onset of stromal autophagy, which produces recycled nutrients to "feed" anabolic cancer cells. However, it remains unknown how autophagy in the tumor microenvironment relates to inflammation, another key driver of tumorigenesis. To address this issue, here we employed a well-characterized co-culture system in which cancer cells induce autophagy in adjacent fibroblasts via oxidative stress and NFκB-activation. We show, using this co-culture system, that the same experimental conditions that result in an autophagic microenvironment, also drive in the production of numerous inflammatory mediators (including IL-6, IL-8, IL-10, MIP1a, IFNg, RANTES (CCL5) and GMCSF). Furthermore, we demonstrate that most of these inflammatory mediators are individually sufficient to directly induce the onset of autophagy in fibroblasts. To further validate the in vivo relevance of these findings, we assessed the inflammatory status of Cav-1 (-/-) null mammary fat pads, which are a model of a bonafide autophagic microenvironment. Notably, we show that Cav-1 (-/-) mammary fat pads undergo infiltration with numerous inflammatory cell types, including lymphocytes, T-cells, macrophages and mast cells. Taken together, our results suggest that cytokine production and inflammation are key drivers of autophagy in the tumor microenvironment. These results may explain why a loss of stromal Cav-1 is a powerful predictor of poor clinical outcome in breast cancer patients, as it is a marker of both (1) autophagy and (2) inflammation in the tumor microenvironment. Lastly, hypoxia in fibroblasts was not sufficient to induce the full-blown inflammatory response that we observed during the co-culture of fibroblasts with cancer cells, indicating that key reciprocal interactions between cancer cells and fibroblasts may be required.
    • Cytokine release syndrome (CRS) following treatment with tebentafusp, a novel bispecific TCR-anti-CD3 directed against gp100, in patients with advanced melanoma

      Shoushtari, A; Middleton, M; Stevens, N; Evans, T; Infante, J; Sznol, M; Anthoney, A; Gupta, Avinash; Woodcock, V; Wiseman, T; et al. (2019)
    • Cytoreductive surgery (CRS) with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) versus standard of care (SoC) in people with peritoneal metastases from colorectal, ovarian or gastric origin: protocol for a systematic review and individual participant data (IPD) meta-analyses of effectiveness and cost-effectiveness

      Gurusamy, K.; Vale, C. L.; Pizzo, E.; Bhanot, R.; Davidson, B. R.; Mould, T.; Mughal, M.; Saunders, Mark P; Aziz, Omer; O'Dwyer, Sarah T; et al. (2020)
      Introduction: There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery. Primary objectives: To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis. Secondary objectives: To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost-utility analysis. Methods and analysis: We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting. Ethics and dissemination: This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal.
    • Cytoreductive surgery for ovarian carcinoma.

      Scott, N A; Schofield, Philip F; Christie Hospital and Holt Radium Institute, Manchester, UK. (1990-05)
    • Cytotoxic chemotherapy and viral infections: the role of acyclovir.

      Anderson, Heather; Sutton, R; Scarffe, J Howard (1984-01)
    • Cytotoxic chemotherapy for advanced, non-resectable colorectal cancer

      Valle, Juan W; Board, Ruth E; Cancer Research UK Department Medical Oncology, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK (2007-10-23)
    • Cytotoxic endocrinopathy: a legacy of insults.

      Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Withington, Manchester, England. (1997-04)
    • Cytotoxicity of L-canavanine in vitro.

      Naha, P M (1981)
      Cytotoxicity of L-canavanive, a structural analogue of L-arginine, was tested by means of (1) inhibition of DNA synthesis in Balb/c-3T3 cell line and (2) inhibition of mitosis in peripheral blood lymphocytes in culture. The cytostatic nature of inhibition caused by L-canavanine was indicated by the complete recovery of cells after withdrawal of the drug.
    • Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation.

      Kim, Joo-Young; West, Catharine M L; Valentine, Helen R; Ward, Timothy H; Patterson, Adam V; Stratford, Ian J; Roberts, Stephen A; Hendry, Jolyon H; Cancer Research UK Groups of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (2004-03)
      BACKGROUND AND PURPOSE: RH1 is a new bioreductive agent that was developed as a cytotoxic agent with selectivity for tumour cells expressing high levels of the enzyme DT-diaphorase (DTD). The aim of the present study was to investigate the cytotoxicity of RH1 in relation to cellular levels of reducing enzymes and any interaction of RH1 with ionizing radiation under oxic and hypoxic conditions. PATIENTS AND METHODS: The MB-MDA231 human breast cancer cell line (WT) and WT cells transfected with the NQO1 gene encoding DTD (the D7 cell line) were used to examine the dependency of RH1's cytotoxicity on cellular DTD activity. The role of the 1-electron reducing enzyme P450 reductase was also studied using a P450 reductase-transfected isogenic cell line (R4). A clonogenic assay was used to investigate the cytotoxicity of RH1 with and without irradiation in air and in nitrogen. In all cases drug exposure was for 3 h. RESULTS: DTD levels were around 300-fold higher in D7 compared to WT and R4 cells. RH1 was cytotoxic at nanomolar concentrations to all the cell lines, and was 2-3 times more toxic in the D7 cells with high DTD than in the other two cell lines. Doses of RH1 was around 2-fold more effective in hypoxic than in oxic WT cells, but not by as much in D7 cells. RH1 did not radiosensitise the cells but showed an additive effect when combined with irradiation under oxic and hypoxic conditions. CONCLUSIONS: RH1 shows high clonogenic cytotoxicity to MDA231 cells with high DTD activity but its selectivity based on the presence of DTD is much less than as shown in previous reports. RH1 showed an additive cell killing effect when combined with irradiation under both oxic and hypoxic conditions.