Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer.

PURPOSE: Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC. MATERIALS AND METHODS: Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity. RESULTS: Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death. CONCLUSION: Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. Methods: 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([18F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [18F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle (i.e. tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Results: Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; p = 0.480 for PD-L1, HR = 0.991; p = 0.989 for PD-1), PFS (HR = 0.813; p = 0.597 for PD-L1, HR = 0.796; p = 0.713 for PD-1) or OS (HR = 0.698; p = 0.405 for PD-L1, HR = 0.315; p = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, p = 0.022) and a trend towards reduced PFS (HR = 2.752, p = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, p = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, p = 0.772, PFS: HR = 0.846, p = 0.766). Conclusion: In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.

Personalising and targeting antiangiogenic resistance: a complex and multifactorial approach.

Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail. Here we review how the dual stromal adaptive patterns determine the mechanisms of escape that go beyond the reprogramming of signal transduction pathways, which obliges us to investigate the tumour as an ecosystem and to develop uni- and multicompartmental models that explain drug resistance involving metabolic and immune reprogramming. We also propose a method for facilitating personalised therapeutic decisions, which uses 18F-fluoromisonidazole-positron emission tomography to monitor the dual stromal response in tumours of individual patients.

Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers.

BACKGROUND AND PURPOSE: Positron emission tomography (PET) with [(18)F]-fluoromisonidazole ([(18)F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [(18)F]-FMISO-PET for head-and-neck cancers (HNC). PATIENTS AND METHODS: Ten patients with inoperable stages III-IV HNC underwent [(18)F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). RESULTS: The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8% respectively. CONCLUSION: A dose escalation up to 79.8 Gy guided by [(18)F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids.

A phase III randomized study of misonidazole plus radiation vs. radiation alone for cervix cancer.

BACKGROUND AND PURPOSE: A randomized-controlled study of radical radiotherapy for cervical cancer with or without the hypoxic sensitizer, misonidazole was conducted from 1981 to 1984 to investigate its therapeutic benefit. PATIENTS AND METHODS: Seventy-three patients were accrued from the Princess Margaret Hospital, and St John Regional Cancer Centre and randomized to either misonidazole (MISO, n = 39) or placebo (P, n = 34) in addition to radiotherapy. MISO was given orally each day 4 h prior to external beam radiation treatment (45Gy to midplane in 20 daily fractions) at a dose of 0.45 g/m(2), as well as during intra-uterine brachytherapy (40Gy). RESULTS: The 10-year overall survival (OS) for the entire group was 46%, and the disease-free survival (DFS) was 39%. The 10-year OS for patients in the MISO arm was 45%, compared to 49% for the P arm (P = 0.89). The corresponding DFS figures were 36 and 43%, respectively, (P = 0.6). Ten patients (14%) developed severe late complications (grade 3 or 4). The 10-year serious late complication rate was 14% for MISO and 12% for P (P = 0.51). CONCLUSIONS: Misonidazole failed to improve the outcome of patients with cervix cancer treated with radiotherapy.

The range of oxygenation in SiHa tumor xenografts.

Tumor cells at very low oxygen tensions are known to be about three times more resistant to killing by ionizing radiation. Since cells at intermediate oxygen tensions (defined here as greater than 0.1% and less than 2% O(2)) show partial radioresistance, they should be a consideration in tumor treatment. In an effort to estimate the extent and range of oxygenation in SiHa human cervical carcinoma xenografts, patterns of cell killing and DNA damage by radiation and two bioreductive drugs, PD-144872 and RSU-1069, were compared to those seen in SiHa cells grown as spheroids. These drugs produce DNA interstrand crosslinks that are largely responsible for cell killing, and the degree of crosslinking increases as the oxygenation is reduced. About 60% of the cells in SiHa xenografts exhibited drug-induced crosslinks, but only about 35% showed extensive crosslinking indicative of hypoxia below 0.1% oxygen. Patterns of toxicity and DNA damage in xenografts were comparable to those of spheroids equilibrated with about 2% oxygen, indicating that most cells in the xenografts exhibit some radioresistance due to lack of oxygen. Similarly, pimonidazole binding indicated that about 60% of the cells in SiHa xenografts were either intermediate in oxygenation or hypoxic, but only about half of those were consistent with extreme oxygen depletion. The apparent size of the population of "intermediately hypoxic" cells has implications for the use of ionizing radiation, hypoxic cell cytotoxins, and other antitumor agents whose cytotoxicity is dependent on cellular oxygen content.

External-beam radiotherapy in the management of liver metastases.

This review discusses the importance of palliation of liver metastases. Although colorectal cancer comprises the majority of patients with metastatic liver disease, a number of other malignancies can be involved. Palliation of metastatic disease to liver has generally not included the use of external-beam radiotherapy because of restricted liver tolerance to radiotherapy. However, more recently, treatment policies have evolved to more generous use of palliative radiotherapy with utilization of tumor boost doses to partial liver volumes. This has resulted in improvement in palliation and a suggestion of improved survival with higher radiotherapy doses, which have been well tolerated by small volumes of liver.

The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study was to determine the incidence of thrombocytosis and its possible impact on survival probability among women with locally advanced cervical carcinoma. METHODS: The database of 294 patients with Stages IIB-IVA cervical carcinoma without periaortic node metastasis who were treated with standardized radiation therapy and concurrent hydroxyurea or misonidazole was analyzed. Pretreatment platelet counts were available for 291 patients who are the subject of this study. RESULTS: Thrombocytosis (platelet count >400 x 10(9)/liter) was present in 86 (29.6%) of the 291 patients. A multivariate Cox proportional hazards model showed that patients without extrapelvic disease and with thrombocytosis had a 55% greater chance of dying than those without thrombocytosis (relative risk = 1.55, 95% confidence interval 1.08-2.21). Patients with thrombocytosis had larger tumors and more frequently had bilateral parametrial involvement, tumor fixation to the sidewall, and positive pelvic lymph nodes than patients without thrombocytosis. Thrombocytosis was not found to be a prognostic factor in patients with positive pelvic nodes. However, in patients with negative pelvic nodes, the presence or absence of thrombocytosis was related to survival. CONCLUSION: Thrombocytosis is a frequent finding among patients with advanced cervical carcinoma and seems to be related to tumor burden. Among patients with locally advanced cervical carcinoma who had negative pelvic nodes, those with thrombocytosis had a poorer survival.

Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide.

BACKGROUND: In animal models carbogen (normobaric 95% oxygen, 5% carbon dioxide) provides significant enhancement of local tumor control with fractionated radiotherapy. This approach to radiosensitization has been evaluated in the treatment of patients with bladder carcinoma using radical radiotherapy. METHODS: Sixty-one patients with locally advanced bladder carcinoma were treated using a Phase II trial delivering radiotherapy to the bladder (50-55 Grays in 20 daily fractions over 4 weeks) with inhalation of carbogen alone in 30 patients and the addition of oral nicotinamide (80 mg/kg) prior to radiotherapy with carbogen in 31 patients. The results from these 61 patients were compared with those from two earlier attempts at hypoxic sensitization: the second Medical Research Council (MRC) hyperbaric oxygen trial in patients with bladder carcinoma and a Phase III trial of misonidazole with radiotherapy in patients with bladder carcinoma performed at Mount Vernon Hospital. RESULTS: Although there was no difference between the hyperbaric oxygen and misonidazole trials, when compared with the two earlier series there was a large, statistically significant difference in favor of those patients receiving carbogen with or without nicotinamide for local control (P = 0.00001), progression free survival (P = 0.001), and overall survival (P = 0.04). CONCLUSIONS: Although the advantage for the carbogen group may be explained in part by changes in radiotherapy practice over the period of the three studies the improvement in local control is sufficiently great to support the hypothesis that hypoxia is important in modifying the control of bladder carcinoma using radiation therapy. Further evaluation of accelerated radiotherapy, carbogen, and nicotinamide in patients with bladder carcinoma is needed in a Phase III trial.

Irradiation with or without misonidazole for patients with stages IIIB and IVA carcinoma of the cervix: final results of RTOG 80-05. Radiation Therapy Oncology Group.

PURPOSE: The purpose of this study was to evaluate tumor response, progression-free survival, local tumor control, patterns of relapse, and toxicity in patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix treated with irradiation or irradiation and misonidazole. This is a report of the final results of the study. METHODS: This study was a prospective randomized Phase III trial performed by the Radiation Therapy Oncology Group (RTOG). Between August 1980 and November 1984, 120 patients with Stages IIIb and IVa squamous cell carcinoma of the cervix were randomized to receive either standard irradiation or standard irradiation and misonidazole. Irradiation consisted of 46 Gy to the pelvis plus a 10 Gy parametrial boost followed by intracavitary brachytherapy or external irradiation boost to the primary tumor. Misonidazole was administered at 400 mg/m2 daily, 2-4 h before irradiation. Patients in the 2 treatment groups were evenly distributed by stage, Karnofsky Performance Status, and positive para-aortic lymph nodes. RESULTS: Sixty-one patients were treated with irradiation alone, and 59 patients received irradiation and misonidazole. Complete response in the pelvis occurred in 44 (75%) of those treated with irradiation and in 38 (64%) of those treated with irradiation and misonidazole. The progression-free survivals were 22% at 5 years for the control group, and 29% at 5 years for the misonidazole group. At the time of last follow-up, 18 patients in the control arm were free of disease, and in the experimental arm, 19 were free of disease. The patterns of failure for those treated with irradiation alone were local-only in 9 patients, distant-only in 8 patients, and local and distant in 11 patients. The patterns of failure for those receiving irradiation and misonidazole were local-only in 3 patients, distant-only in 8 patients, and local and distant in 8 patients. The maximum toxicity experienced per patient was grade 3 in 18%, grade 4 in 8%, and no grade 5 toxicity for those treated with irradiation alone compared to 8%, 2%, and 2%, respectively, for the experimental arm. CONCLUSION: There were no statistically significant differences in pelvic response, disease-free survivals, patterns of failure, or toxicity for the irradiation alone group or for the irradiation and misonidazole group as administered in this study for patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix.

Meta-analytic re-evaluation of misonidazole in the treatment of high grade astrocytoma.

BACKGROUND: The clinical effects of the radiation sensitizer, misonidazole, in the treatment of high grade astrocytoma are equivocal based on available clinical trial data. A meta-analysis was performed in order to evaluate the impact of this compound on treatment outcome for this disease. METHODS: One year survival data derived from over 1,700 patients enrolled in 9 randomized clinical trials were analyzed using the meta-analytic techniques previously described by Peto et al. This analysis compared the proportion of patients surviving one year treated with misonidazole sensitized radiation therapy (+/- chemotherapy) versus radiation alone (+/- chemotherapy). RESULTS: A summary odds ratio was calculated following a statistical analysis showing a lack of heterogeneity among the included studies in terms of their estimate of effect. The calculated Peto odds ratio was 0.92 with a 95% confidence interval of 0.77-1.09. These data indicate that misonidazole treatment is associated with an approximately 8% improved 1 year survival compared with non-misonidazole treatment arms. This odds ratio increased to 0.87 when only those trials using "conventional" radiation therapy schedules were analyzed. CONCLUSION: This analysis suggests that misonidazole may contribute to improved 1 year survival in patients with high grade astrocytoma and that the magnitude of this improvement may be comparable to that seen with the use of chemotherapy in this patient group.

Hypoxic sensitizer and cytotoxin for head and neck cancer.

Tumour hypoxia is well recognised as a major factor contributing to radioresistance. This article examines the role of hypoxia in influencing the treatment outcome following radiotherapy (RT), and reviews the rationale and results of clinical trials that utilise hypoxic sensitizers or cytotoxins in the treatment of head and neck carcinoma. Histologic evidence for tumour hypoxia in human neoplasms was first reported in 1955. Since then, direct measurement by microelectrodes has revealed heterogeneity in intratumoural oxygen concentrations, and low oxygen concentrations are associated with poor local-regional control by RT. These findings coupled with the result of nuclear imaging studies employing radiolabelled imidazoles, provide strong evidence for the existence of tumour hypoxia which influences RT treatment outcome. Hyperbaric oxygen (HBO) trials for head and neck cancer, conducted in the early 1970s, demonstrated that HBO improved local control and survival rates in patients with head and neck cancer receiving radiotherapy (RT). Since the mid-1970s, clinical research in overcoming tumour hypoxia was mainly centred on the use of nitro-imidazoles as hypoxic cell sensitizers. However, the results from several major clinical trials remain inconclusive. Specifically, the Radiation Therapy Oncology Group (RTOG) misonidazole head and neck trial (298 patients) showed no benefit. The Danish misonidazole trial (626 patients) showed no overall benefit, however positive results were observed in a subgroup (304 pharyngeal cancer patients). Although the European Organisation for Research and Teaching of Cancer (EORTC) misonidazole trial with hyperfractionated RT showed no benefit, the Danish nimorazole trial demonstrated an overall benefit in survival as well as local control. The European etanidazole (ETA) trial (374 patients) showed no advantage of adding the drug to RT. The RTOG ETA trial (504 patients) showed no global benefit. However, positive results were observed in a subset of patients with early nodal disease (197 patients). In addition, a recent meta-analysis by Overgaard, utilising pooled results in the literature demonstrated that modification of tumour hypoxia significantly improved local-regional control in head and neck cancers with an odds ratio of 1.23 (95% confidence limits 1.09 to 1.37). Hypoxic cytotoxins, such as tirapazamine, represent a novel approach in overcoming radioresistant hypoxic cells. Tirapazamine is a bioreductive agent which, by undergoing one electron reduction in hypoxic conditions, forms cytotoxic free radicals that produce DNA strand breaks causing cell death. In vitro and in vivo laboratory studies demonstrate that tirapazamine is 40 to 150 times more toxic to cells under hypoxic conditions as compared to oxygenated conditions and that tirapazamine is superior to ETA in enhancing fractionated irradiation in mouse SCCVII and other tumour types with an enhancement ratio of 1.5 to 3.0. Phase I studies demonstrated that therapeutic doses of tirapazamine can be given safely. A multi-institutional phase II trial using tirapazamine with concurrent RT for head and neck cancer is now in progress.

The EORTC randomized trial on three fractions per day and misonidazole in advanced head and neck cancer: prognostic factors.

In trial no. 22811 on a randomized comparison of multiple fractions per day (MFD), with or without misonidazole, to conventional fractionation in advanced head and neck cancer, a large number (523) of patients was entered in a short period of time. No differences in treatment results were obtained, but the study created an important database, allowing for detailed evaluation of the most important factors influencing prognosis. In univariate analysis, factors significantly influencing survival and locoregional control were: performance status, histological differentiation, tumor site, tumor and nodal staging, and tumoral and nodal volume. In multivariate analysis, significant factors for survival were nodal involvement, tumor stage, performance status, and tumor site. Significant factors for locoregional control were nodal involvement and total tumor burden. This analysis suggests that total tumor burden (volume) should be included in the interpretation of treatment results in head and neck cancer.

Comparing the anti-tumor effect of several bioreductive drugs when used in combination with photodynamic therapy (PDT).

PURPOSE: To compare the effect on the RIF-1 murine sarcoma of nine bioreductive agents from five different classes when used in combination with either photodynamic therapy or clamping. METHODS AND MATERIALS: RIF-1 tumors implanted intradermally in C3H mice were treated with either 50J photodynamic therapy or with 120 min clamping in combination with either misonidazole, pimonidazole, metronidazole, nimorazole, RB6145, RSU1069, SR4233, mitomycin-C, or RB90740. The tumors were measured 3 times-per-week until reaching 4 x their initial treatment volume. RESULTS: RSU1069 produced the greatest anti-tumor activity in combination with both photodynamic therapy and clamping. RB6145 also substantially enhanced the effect of photodynamic therapy and clamping whereas misonidazole induced a smaller, but significant increase. Mitomycin-C had no effect under clamped conditions, but greatly increased the tumorcidal effect of photodynamic therapy. Mitomycin-C also induced an effect when given with light alone. None of the other agents showed any augmentation of the tumor cell killing induced by photodynamic therapy. CONCLUSION: Of the bioreductive agents studied RSU1069, RB6145 and mitomycin-C showed the greatest anti-tumor response in combination with photodynamic therapy.

Bioreduction of RSU 1069 and mitomycin C after dearterialization.

RSU 1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol) and Mitomycin C (MMC) have both been shown to be directly cytotoxic to hypoxic cells. Repeat and transient dearterializations of a liver tumour would cause its cells to become intermittently hypoxic. In this experiment the therapeutic gain of RSU 1069 and MMC was evaluated when combined with either a single or repeat dearterializations of a transplanted liver tumour. The tumour growth during the first 6 days was significantly delayed when the administration of RSU 1069 (40 mg kg-1, i.p.) was followed 15 minutes later by a single dearterialization for 2 hours compared with sham operation (P = 0.0369) or either treatment alone (P = 0.0142 vs RSU 1069 alone and P = 0.0031 vs a single dearterialization for 2 hours alone). Furthermore, RSU 169 administered 15 min prior to a single dearterialization for 2 hours is more effective to retard tumour growth than MMC either alone (P = 0.0198) or with the same period of dearterialization (P = 0.0326). Repeat dearterializations (2 hours/day) during 5 days effectively retarded the growth of the tumour by itself (P = 0.015 vs sham operation). A larger growth delay was obtained when RSU 1069 was administered 15 min before the first dearterialization (P = 0.009 vs sham operation), though the growth delay between those two groups was not significant (P = 0.07). Survival time was significantly prolonged when repeat dearterializations were combined with RSU 1069 (P = 0.007 vs sham operation; P = 0.0009 vs RSU 1069 and P = 0.003 vs repeat dearterialization alone).(ABSTRACT TRUNCATED AT 250 WORDS)