Biological evaluation of new potential anticancer agent for tumour imaging and radiotherapy by two methods:^99mTc-radiolabelling and EPR spectroscopy

Abstract

Recently, a new class of in vitro and ex vivo radiotracers/radioprotectors, the nitroxyl-labelled agent 1-ethyl-1-nitroso–3-[4-(2,2,6,6–tetramethylpiperidine-1-oxyl)]-urea (SLENU), has been discovered. Our previous investigations demonstrated that SLENU is a low-molecular-weight stable free radical which is freely membrane permeable, easily crosses the blood brain barrier and exhibited in/ex vivo the lowest general toxicity and higher anticancer activity against some experimental tumour models. Further investigation was aimed to develop a 99mTc-labelled SLENU (97%) as a chelator and evaluate its labelling efficiency and potential use as a tumour seeking agent and for early diagnosis. Tissue biodistribution of 99mTc-SLENU was determined in normal mice at 1, 2 and 24 h (n = 4/time interval, route of administration i.v.). The distribution data were compared using male albino non-inbred mice and electron paramagnetic resonance investigation. The imaging characteristics of 99mTc-SLENU conjugate examined in BALB/c mice grafted with Ehrlich Ascitis tumour in the thigh of hind leg demonstrated major accumulation of the radiotracer in the organs and tumour. Planar images and auto-radiograms confirmed that the tumours could be visualized clearly with 99mTc-SLENU. Blood kinetic study of radio-conjugate showed a bi-exponential pattern, as well as quick reduced duration in the blood circulation. This study establishes nitroxyls as a general class of new spin-labelled diagnostic markers that reduce the negative lateral effects of radiotherapy and drug damages, and are appropriate for tumour-localization.

Options for reducing oxidative toxicity of L-dopa by combination with synthetic or natural radical protectors

“…In vitro was detected the synergistic effect of the spin-labeled nitrosourea 1-ethyl-3-[4-(2,2,6,6tetramethylpiperidine-1-oxyl)] -1-nitrosourea (SLENU) on the cytotoxicity of bleomycin and farmorubicin in human lymphoid leukemic tumor cells [21]. Recent studies have demonstrated the protective effect of SLENU against drug-induced oxidative stress in liver and blood in experimental animals [22,23].…”

Comparative Real Time EPR Investigation of Natural and Synthetic Antioxidants: As Potential Anticancer Agents and Radio-protectors

“…Searching for potential combination of microbial/ herbal compounds and synthetic drugs at pharmacological processes, in the field of radical-scavenging biology and reduction of ROS/RNS levels, considerably has increased during the past 10 years 12,3 . Several spin-labelled nitrosoureas, analogues of the anticancer drug CCNU, were tested for their protective and anticancer activity and as radio-modulating agents with low toxicity 13,14 . Nitroxyl-containing nitrosourea compounds showed in vitro good antioxidant activity 15 and higher alkylating 15,16 , and twice lower carbamoylating activity 16 comparing to their analogue, CCNU.…”

Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

“…Many authors indicate that the oxidative stress is a direct or indirect result of ROSmediated damage on biological macromolecules and a major factor not only for carcinogenesis, but also for neurodegeneration, cardiovascular disease, inflammation, atherosclerosis, diabetes, aging, etc. (14)(15)(16)(17)(18)(19)(20).…”