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Hypoxic Tumors (hypoxic + tumor)
Selected AbstractsSynthesis and evaluation of 2-, 4-, 5-substituted nitroimidazole-iminodiacetic acid- 99mTc(CO)3 complexes to target hypoxic tumorsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2010Madhava B. Mallia Abstract Determination of hypoxia in tumor is an important problem in the clinical management of cancer. Towards this, a series of differently substituted nitroimidazoles, viz. 2-nitro, 4-nitro and 5-nitroimidazole iminodiacetic acid (IDA) derivatives were synthesized and radio-labeled with a [99mTc(CO)3(H2O)3]+ core. The corresponding 185/187Re(CO)3 analogue of 2-nitroimidazole-IDA- 99mTc(CO)3 complex was also prepared and characterized to elucidate the mode of bonding between the ligand and the M(CO)3 core (M=99mTc, 185/187Re). All the three nitroimidazole-IDA- 99mTc(CO)3 complexes could be prepared in over 95% yield determined by HPLC. The three complexes were then evaluated in a suitable animal model bearing tumor. Though the in vivo accumulation of complexes in hypoxic tissue is governed by factors such as lipophilicity, charge, etc., the variation in accumulation in hypoxic tissue, in the present case, could be explained by considering the reported values of single electron reduction potential of the respective nitroimidazoles. Among the three derivatives studied, the 2-nitroimidazole-IDA- 99mTc(CO)3 complex produced the best result followed by the 5-nitroimidazole complex. Copyright © 2010 John Wiley & Sons, Ltd. [source] Quinoxaline 1,4-dioxides: Hypoxia-selective therapeutic agentsMOLECULAR CARCINOGENESIS, Issue 4 2002Mona Diab-Assef Abstract A problem that confronts clinicians in the treatment of cancer is the resistance of hypoxic tumors to chemotherapy and radiation therapy. Thus, the development of new drugs that are toxic to hypoxic cells found in solid tumors is an important objective for effective anticancer chemotherapy. We recently showed that the heterocyclic aromatic N-oxides, quinoxaline 1,4-dioxides (QdNOs), are cytotoxic to tumor cells cultured under hypoxia. In this study, we evaluated the hypoxia-selective toxicity of four diversely substituted QdNOs and determined their effect on the expression of hypoxia inducible factor (HIF) 1, in the human colon cancer cell line T-84. The various QdNOs were found to possess a 50- to 100-fold greater cytotoxicity to T-84 cells cultured under hypoxia compared with oxia. Interestingly, the hypoxia cytotoxicity ratio (HCR), the ratio of equitoxic concentrations of the drug under aerobic/anoxic conditions, was highly structure related and depended on the nature of the substituents on the QdNO heterocycle. The most cytotoxic 2-benzoyl-3-phenyl-6,7-dichloro derivative of QdNO (DCQ) was potent at a dose of 1 ,M with an HCR of 100 and significantly reduced the levels of HIF-1, transcript and protein. The 2-benzoyl-3-phenyl derivative (BPQ) had a hypoxia potency of 20 ,M and an HCR of 40. By contrast, the 2-aceto-3-methyl and the 2,3-tetramethylene (TMQ) derivatives of QdNO were much less cytotoxic under hypoxia (HCRs of 8.5 and 6.5, respectively) and reduced the expression of HIF-1, mRNA to a much lesser extent. Because the nonchlorinated analogue BPQ did not demonstrate behavior similar to that of DCQ, we hypothesize that the C-6, C-7-chlorine of DCQ might play a significant role in the selective hypoxic cytotoxicity of the drug. © 2002 Wiley-Liss, Inc. [source] Head and Neck Cancer: The Importance of Oxygen ,THE LARYNGOSCOPE, Issue 5 2000David J. Terris MD Abstract Objectives To use recently introduced polarographic technology to characterize the distribution of oxygenation in solid tumors, explore the differences between severe hypoxia and true necrosis, and evaluate the ability to predict treatment outcomes based on tumor oxygenation. Study Design Prospective, nonrandomized trial of patients with advanced head and neck cancer, conducted at an academic institution. Methods A total of 63 patients underwent polarographic oxygen measurements of their tumors. Experiment 1 was designed to determine whether a gradient of oxygenation exists within tumors by examining several series of measurements in each tumor. Experiment 2 was an analysis of the difference in data variance incurred when comparing oxygen measurements using oxygen electrodes of two different sizes. Experiment 3 compared the proportion of tumor necrosis to the proportion of very low (,2.5 mm Hg) polarographic oxygen measurements. Experiment 4 was designed to explore the correlation between oxygenation and treatment outcomes after nonsurgical management. Results No gradient of oxygenation was found within cervical lymph node metastases from head and neck squamous cell carcinomas (P > .9). Tumor measurements achieved with larger (17 ,m) electrodes displayed smaller variances than those obtained with smaller (12 ,m) electrodes, although this difference failed to reach statistical significance (P = .60). There was no correlation between tumor necrosis and the proportion of very low (,2.5 mm Hg) oxygen measurements. There was a nonsignificant trend toward poorer locoregional control and overall survival in hypoxic tumors. Conclusions Hypoxia exists within cervical lymph node metastases from head and neck squamous carcinomas, but the hypoxic regions are distributed essentially randomly. As expected, measurements of oxygen achieved with larger electrodes results in lowered variance, but with no change in overall tumor mean oxygen levels. Polarographic oxygen measurements are independent of tumor necrosis. Finally, oxygenation as an independent variable is incapable of predicting prognosis, probably reflecting the multifactorial nature of the biological behavior of head and neck cancers. [source] Tumor hypoxia: A target for selective cancer therapyCANCER SCIENCE, Issue 12 2003Shinae Kizaka-Kondoh Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO2<0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties. [source] | ||||||||||