Abstract
A series of compounds in which a 2-nitroimidazole is linked to a DNA intercalating phenanthridine moiety has been synthesised. Previously, three such compounds, termed nitroimidazole-linked phenanthridines or NLPs, were tested in vitro and showed a greatly enhanced molar efficiency as hypoxic cell radiosensitisers and cytotoxins compared with the untargeted 2-nitroimidazole, misonidazole. Since the cytoxicity of these compounds was shown to be inversely proportional to linker chain length while radiosensitising ability was dependent of it, compounds with five and six carbons in the chain were synthesised in an attempt to lower the toxicity of the drugs while increasing their ability to 'scan' DNA for target radicals. These compounds and a comparison series of n-alkylated phenathridinium ions have been characterised and evaluated in vitro using Chinese hamster ovary and V79 cells and their effects compared with misonidazole. Based on in vitro results, one member of the series was selected and evaluated in vitro using a V79 spheroid tumour model and in vivo using an SCCVII transplantable tumour system. These studies have demonstrated the potential utility of this class of compound.
Highlights
All of the NLP or P compounds gave similar characteristic UV/visible absorption spectra which indicated that the compounds were stable when dissolved in phosphate-buffered saline (PBS) and stored at either 4°C or room temperature for at least 1 week
Highperformance liquid chromatography (HPLC) analysis confirms the compounds are stable in growth medium at 37°C for a similar length of time
The value of the partition coefficient is at a maximum with the compound which has the shortest chain linking the nitroimidazole to the phenanthridine, two carbons, 2-NLP-2 (NLP-2), decreases to a minimum with the four-carbon linker compound, 2-NLP-4 (NLP-3), and begins to rise again as the chain length is increased further to five and six carbons (Table I)
Summary
The cells used in most of the in vitro experiments were Chinese hamster ovary cells (CHO) subline AA8-4 originally obtained from Dr L.H. Thompson, Lawrence Livermore Laboratory, Livermore, CA, USA, which were maintained in tissue culture flasks in a-minimal essential medium (a-MEM). Since CHO cells do not readily form multicellular spheroids, the Chinese hamster lung fibroblast line V79 was employed in the spheroid studies. This line was obtained from Dr I.F. Tannock of The Ontario Cancer Institute. These cells grow well as monolayers and in suspension culture and were routinely maintained in plastic flasks under the same conditions as the CHO cells. Spheroids were used in experiments when they reached a size of 600-800 ym as determined microscopically using a calibrated eyepiece
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