Abstract
The effect of the maturation-inducing polar solvent, hexamethylene bisacetamide (HMBA), on the radiosensitivity of two human tumour cell lines (clone A, a colon carcinoma; and EJ, a bladder carcinoma) was investigated. Exposure of clone A or EJ cells to HMBA resulted in a concentration-dependent increase in doubling time, a decreased plating efficiency and changes in cell morphology, which are consistent with the formation of a better-differentiated phenotype. Growth of clone A cells in 2 or 3 mM HMBA, followed by irradiation and plating into HMBA-free medium, resulted in a significant enhancement in radiosensitivity, as determined by colony-forming ability. A similar increase in radiosensitivity was detected for EJ cells; however, for these cells a concentration of 7 mM HMBA was required. The increased radiosensitivity caused by HMBA was observed primarily in the low-dose, shoulder region of the gamma-ray cell survival curves for both cell lines, which is reflected by an increase in the alpha component of the survival curve with essentially no effect on beta. These data indicate that HMBA can radiosensitise human tumour cells at concentrations and for exposure periods that can be achieved in the clinic.
Highlights
The elimination characteristics of hexamethylene bisacetamide (HMBA) suggest that it may be especially suited for treatment of some bladder cancers (Rifkind et al, 1988). In light of this encouraging human pharmacokinetic data, we have investigated the effects of HMBA on the radiosensitivity of two human tumour cell lines derived from colon and bladder (EJ) carcinomas
The increase in culture doubling time was accompanied by a decrease in plating efficiency (Table I), a decrease in cell culture saturation density and changes in cell morphology, which are characteristic of the formation of a better differentiated phenotype (Spremulli & Dexter, 1984)
Previous studies using clone A cells have shown that the conversion to a better differentiated phenotype as a result of exposure to NMF, DMF or sodium butyrate is accompanied by an increase in the cytotoxicity induced by ionising radiation (Leith et al, 1982, 1985; Arundel et al, 1985)
Summary
Clone A cells, originally isolated from a human colon adenocarcinoma, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum, buffers and antibiotics, as described by Leith et al (1982). EJ cells, isolated from a spontaneously occurring human bladder carcinoma, were obtained from the American Type Culture Collection (Rockville, MD, USA) and grown in McCoy's 5A medium containing 10% fetal bovine serum, buffers and antibiotics. Clone A and EJ cells were seeded into 25 or 75 cm tissue culture flasks at least 24 h before being used in an experiment. HMBA (Sigma Chemical Company, St Louis, MO, USA) was dissolved in solution A (8 g NaCl, 0.4 g KCl, 1 g d-glucose, 0.35 g NaHCO3 per litre of water) to a stock concentration of 200 mM and stored in the dark at 4°C. The appropriate volume of stock HMBA solution was added to cultures for a specified time. Irradiations were performed using a "'CS source, with a dose rate of 4.5 Gy min-'
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