Potentiation of combined BCNU and hyperthermia by pH reduction in vitro and hypertonic glucose in vivo in the BT₄ rat glioma

Abstract

In vitro studies have shown enhanced cell killing of BCNU and hyperthermia at acutely lowered pH. In animals hypertonic glucose i.p. has repeatedly been demonstrated to reduce intratumoral pH. Effect of hyperthermia (43°C for 45 min), or BCNU (3.33 μg/ml or both on BT₄C cells were investigated in vitro, with pH 7.5, 7.0 and 6.5 in the medium during treatment. The effect of elevated glucose concentration in the medium (20 mmol/1) during treatment with hyperthermia, or BCNU, or both, was also investigated at pH 7.5. BD IX rats with transplanted BT₄A or BT₄An tumours on the hind foot were treated with BCNU i.p., locally applied water bath hyperthermia (44°C for 45 min) or both, with or without previous glucose (6 g/kg i.p. 2 h before treatment). In vitro: low pH markedly increased cell killing by combined BCNU and hyperthermia, but pH had only a minor influence on treatment with BCNU or hyperthermia alone. Increased glucose concentration in the medium did not influence the effect of BCNU alone, hyperthermia alone, or BCNU and hyperthermia. In vivo: glucose reduced the effect of BCNU alone on BT₄A tumours, but did not influence the treatment results with hyperthermia alone. However, glucose enhanced the effect of combined BCNU and hyperthermias. The effect on BT₄An tumours of BCNU or hyperthermia alone were not affected by glucose, but glucose markedly enhanced the tumour effect of combined BCNU and hyperthermia. Hyperglycaemia seems to be a promising method to increase the benefit of combined hyperthermia and BCNU. However, glucose-induced altered tumour circulation could hamper the potential benefit by decreased drug uptake.

Key Words:

• BCNU
• hyperthermia
• glucose
• pH.