An overview of the initial experience with AK-2123 as a hypoxic cell sensitizer with radiation in the treatment of advanced head and neck cancers.

PURPOSE: AK-2123 (Senazole) is a nitrotriazole with a reported potential for hypoxic cell sensitization. The present study was conducted to evaluate hypoxic cell potentiation in patients with advanced head and neck cancer treated with discontinuous accelerated hyperfractionated radiation. METHODS AND MATERIALS: Histologically proven unresectable oro-pharyngeal cancers Stage T3-4, NO-3 and M0 were randomly allocated to receive discontinuous accelerated hyperfractionated radiation alone or with AK-2123. AK-2123 (880 and 990 mg) was administered as an i.v. infusion between the first and second fraction of radiation for 10 days in two groups of patients. Initial response as a surrogate end point has been analyzed for comparison and documented for follow-up status. RESULTS: A 100% complete response was observed in both the AK-2123-treated groups (880 mg and 990 mg), while a 44.4% complete response was observed in the control group. There were no treatment-related deaths. Neurotoxicity was not reported. CONCLUSION: AK-2123 (Senazole) when administered with discontinuous accelerated hyperfractionated radiation showed a significant potentiation that, therefore, requires further evaluation.

Hypofractionated external radiation with high and low dose rates in the treatment of advanced cancer of the cervix.

Thirteen patients with cancer of the cervix Stage IIIb (heavy) were treated with high (9) and low (4) dose rates, once a week. A total dose of 4200 cGy was delivered over 7 weeks with a fraction size of 600 cGy. Six of nine patients showed complete response following high dose rate hypofractionated radiation. It is felt that synchronization of cells into a sensitive phase during low dose rate radiation is not the determinant of outcome even when duration of treatment is only 5 to 6 hours.

Expression of p53 and lactate dehydrogenase in murine fibrosarcoma following exposure to gamma-radiation.

Radiation-induced alterations in the levels of p53 and lactate dehydrogenase activities were studied in fibrosarcoma, following exposure to different doses of gamma-irradiation (2-10 Gy). The levels of p53 were elevated in the cytoplasm, while the lactate dehydrogenase activity in tumor tissue was considerably decreased.

Redox reactions of sanazole (AK-2123) in aqueous solutions: a pulse radiolysis study.

The redox chemistry of sanazole, an efficient hypoxic cell radiosensitizer, generally referred to as AK-2123, was studied by pulse radiolysis with eaq-, CO2-., 2-propanol radicals and CH2OH radicals. AK-2123 reacts with eaq-, CO2-. and 2-propanol radicals at almost diffusion-controlled rates, producing a nitro radical anion (lambda max = 290 nm) within a few microseconds. The decay kinetics of the radical anion was independent of the pH. The radical anion reacts with oxygen with a rate constant of 3.4 x 10(6) dm3 mol-1 s-1. An electron-transfer reaction was observed from the thymine radical anion to AK-2123. From redox equilibria with methyl viologen, the one-electron reduction potential of AK-2123 in aqueous solution, determined by pulse radiolysis, was estimated to be -0.33 +/- 0.02 V vs. NHE. Depletion of intracellular nonprotein thiols did not mitigate the radiosensitizing affect of the hypoxic radiosensitizer, AK-2123.

Capillary perfusion--a study in two groups of radiated patients for cancer of head and neck.

Laser Doppler velocitometry is novel non-invasive technique to assess cutaneous microcirculation. Patients undergoing radiation therapy for head and neck cancer with convention and accelerated fraction action were evaluated under normal condition before and after radiation. A total of 70 sites in group A (conventional fractionation) and 35 sites in group B (accelerated fractionation were evaluated. Increase in perfusion was noted in patients undergoing radiation with accelerated fractionation.

A clinical study to assess chlorpromazine as hypoxic cell sensitizer in head & neck cancer treated with conventional radiation.

A randomized prospective study was conducted to evaluate the effectiveness of chlorpromazine as a sensitizer of radiation in advanced head and neck cancers. Patients with unresectable laryngopharyngeal cancers except glottic cancers, with histologically proven squamous cell carcinoma staged III and IV were accrued for the study. Patients received radiation to a total dose of 6000 cGy in six weeks in both the groups except that patients in the study group received 50 mgs Chlorpromazine (CPZ) in divided doses. Fourteen of 20 patients showed complete response in the control group whereas 34 of 38 patients in chlorpromazine treated group had complete regression of the tumour (p = 0.016). The survival was (p = 0.08) better in patients receiving CPZ. This preliminary study shows beneficial effects of chlorpromazine. No adverse effects due to chlorpromazine in conjunction with radiation were documented.

Assessment of chlorpromazine as radiation sensitizer and protector.

In vitro studies of chlorpromazine (CPZ) a popular anti-psychotic drug has shown radiation sensitizing effects at higher celluar concentration and protective effect at a lower concentration. The present study was designed to evaluate both sensitizing and protective effects in the treatment of advanced cancer of the cervix treated with hypofractionated external radiation and intratumoural injection of chlopromazine. Twenty patients were treated with intratumoural CPZ and radiation, while, 23 patients received radiation alone. A 52.94% complete response was noted in CPZ arm while 39.1% complete response in the control. A trend towards improved response is seen in CPZ group. Similarly patients who received CPZ showed significantly low proctitis rates.

Programmed cell death as a prognostic indicator for radiation therapy in cervical carcinoma patients: a pilot study.

PURPOSE: In clinical practice, radiation therapy often fails in cervical carcinoma stage IIIB and there is a need to develop a predictive assay for prognosis of radiation treatment outcome in cancer patient. We have attempted to evaluate the relevance of changes in Membrane Fluidity (MF) and associated apoptotic cell death in cervical cancer cells after first fractionated dose of radiation therapy to treatment outcome of stage IIIB cervical carcinoma patients. MATERIALS AND METHODS: Biopsies of 15 patients with histologically proven cervix cancer were collected from the patients before and 24 h after first fractionated radiation dose of 2 grays (Gy). Cell suspension made in Dulbecco's Modified Eagle's Medium (DMEM) were used for further investigations and cell suspension of cervix cancer patient were used to measure MF by fluorescence polarization method and apoptotic index (AI) was determined by Tdt dUTP Nucleotide End Labeling (TUNEL) assay. RESULTS: A substantial increase in MF and AI was observed in cervical cancer cells irradiated ex vivo . A significant correlation ( P P > 0.1) was detected between changes in MF and treatment outcome of patients. CONCLUSION: Preliminary results showed significant change in MF and a marked increase in percentage apoptosis of cervix cancer cells irradiated ex vivo . The changes in AI after first fractionated dose of radiotherapy in cervical carcinoma patients may provide a predictor of prognosis for radiotherapy in uterine cervical carcinoma patients.

A phase I trial of tocoferol monoglucoside in patients undergoing hemi-body radiation.

PURPOSE: To evaluate Tocoferol monoglucoside (TMG), a water soluble vit. E. in a phase I trial, as a radiation protector in those undergoing hemi-body radiation for disseminated disease. MATERIALS AND METHODS: Patients scheduled to receive modified hemi-body radiation were accrued for the study. Patients not only had disseminated skeletal disease but, were heavily pretreated Seven patients were accrued for the study. Patients received 1 and 2 gms of TMG. 30-40 minutes before hemibody radiation. A dose of 600 cGy was delivered on telecobalt equipment at mid plane. Immediate Toxicities were evaluated as well as response to pain. RESULTS: All the seven patients underwent radiation uneventfully. There was no drug related toxicity. Pain relief was adequate. CONCLUSION: Tocoferol monoglucoside an effective antioxidant with no significant acute toxicity, when administered in a dose of 1 or 2 gms per oral route. TMG being water-soluble can have global antioxidant and radio protective effects. This needs further clinical evaluation.

The response of skin microcirculation to hyperthermic stress in tumour patients.

Hyperthermia and its effect on tissues are topics of great interest to scientists working in the area of radiation biology and medicine. It has been shown by many workers, that blood flow in malignant tissue displays a different response to heating than that in normal tissue. Initially, the blood flow in tumour tissue is greater than that in normal tissue, and when heat is applied there is an increase in blood flow. The extent of the increase in flow with increasing temperature is greater in normal tissue than in tumour tissue. In our laboratory we studied the effect of temperature on skin blood flow. The skin overlying tumour tissue was compared with skin with no underlying abnormality in cancer patients, and with the skin in healthy control subjects. The instrument used was a Laser Doppler Perfusion Monitor, Pf3 (Perimed, Stockholm, Sweden). We found that the skin overlying tumour tissue showed higher basal perfusion than the skin at the contralateral site with no underlying abnormality. The skin above tumour tissue showed a reduced perfusion response to an increase in temperature (vascular sluggishness) compared to skin at the contralateral site and skin in healthy controls. The reduction in thermal response depends on the size of the tumour.

Membrane oxidative damage and apoptosis in cervical carcinoma cells of patients after radiation therapy.

This article describes evaluation of plasma membrane fluidity and intracellular SOD with relation to apoptotic death of cervical carcinoma cells after radiation therapy. Cells from biopsies of cancer patients (stage IIIB) prior to and 24 h after radiation dose of 2 Gy were examined. Plasma membrane fluidity, measured by fluorescence polarization of DPH incorporated into lipid bilayer and superoxide dismutase (SOD) activity, determined by epinephrine method, showed significant decrease but per cent apoptotic cells, as determined by annexin-V and TUNEL methods, were found increased by two folds after radiotherapy. It is suggested that decrease in DPH polarization in membrane, reduction in SOD activity and increased apoptosis in cervical cells of cancer patients treated with radiation may be consequent to oxidative damage induced by reactive oxygen species (ROS), which may have implications in developing predictive protocol in cancer radiotherapy.

Genetic alterations in the coding region of the bak gene in uterine cervical carcinoma.

A significant frequency of mutations (six missense and one silent) was found, for the first time, at the coding region of the bak gene (exons 3, 4 and 6) in 42 carcinomas of the uterine cervix, while no mutations were detected in 32 non-neoplastic cervix tissues. Bak mutations were observed more frequently in the advanced stage and mutated cancer tissues were more resistant to radiotherapy, although trends were not statistically significant because of small sample size.