Tumour-growth inhibition by induced hyperglycaemia/hyperlactacidaemia and localized hyperthermia

Abstract

The present study was undertaken to exploit pathophysiological properties of solid tumours for a tumour-specific therapy. Experiments were carried out on DS-sarcomas implanted s.c. in the hind foot dorsum of Sprague Dawley rats. Treatment strategies included tumour acidification, lactate accumulation and disturbance of the microcirculation by induced systemic hyperglycaemia/hyperlact-acidaemia (15-25/10 mmol/L; for 60 min) as well as localized hyperthermia (water-bath; 43 degrees C, 30 min.). A special infusion solution was developed for the systemic treatment containing glucose, lactic acid and organic buffer without inorganic ions. Growth kinetics of tumour volume and animal survival were taken as endpoints in order to quantify therapeutic efficiency. After a single treatment with combined modalities, i.e., with hyperglycaemia/hyperlactacidaemia and hyperthermia, approximately 50% of the tumours showed complete remission in three independent series of experiments; around 40% of the animals survived more than two months. In the untreated control group, all animals died from the disease within 10-15 days after tumour implantation. The overall effect on tumour volume changes of the combined therapy was supra-additive compared to that of treatment with hyperthermia or hyperglycaemia/hyperlactacidaemia alone. However, treated animals either showed a dramatic response to the combination of treatments with complete tumour remission or hardly responded at all, justifying a subdivision into responders and non-responders. Pathophysiological mechanisms responsible for this behaviour have to be elucidated in future studies. Nevertheless, the present study represents an approach to an efficient tumour therapy with a potential application in clinical oncology in the not too distant future.

Hyperlactacidaemia in isolated hyperthermic perfusion of tumour bearing rat limbs: a study of feasibility using a novel infusion solution

“…A lthough these animals died earlier than expected too, most of their tumours showed an extensive necrosis af ter hyper-thermic perfusion with hyperlactaci daemia. A volume shrinkage of the DS-sarcomas could be proved, supporting the results of a previous study (Mueller-Klieser et al 1996).…”

“…A fter the musculature had reached the demanded temperature of 38 and 40 ë C, respectively, perfusion was continued for a further 60 min in all groups. In groups III, IV and V the desired level of hyperlactacid aemia was achieved by adding adequate amounts of the previously described inf usion solution of lactic acid, glucose and Tris bu er to the perfusate (Mueller-Klieser et al 1996). A fter removal of the cannulas at the end of the perfusion, the femoral vessels were repaired with 10/0 non-absorbab le single sutures, while the wound was closesd applying absorbable running sutures.…”

“…Vaupel 1990). A lso, a growth-inhib itory e ect of exogenous lactate on cultured tumour cells had been demonstrated (Marx et al 1988) that gave rise to the development of a novel inf usion solution of lactic acid, glucose and Tris bu er for systemic use (Mueller-Klieser et al 1996). Hyperlactacidaemia induced by this solution in combination with localized hyperthermia reduced the growth of DS-sarcomas implanted in rats.…”

Manipulating extracellular tumour pH: an effective target for cancer therapy

“…meta-Iodobenzylguanidine is one of the inhibitors of mitochondrial complex 1, acting as proton extrusion inhibitors (or hyperglycemia) and then decreasing pH i in cancer cells. 100,[109][110][111] However, this drug is normally used as a radioiodine therapy agent, and the dose used for radioiodine therapy is not high enough to perform a strong inhibition on proton transportation. Dinitrophenol (DNP), a new type of chemotherapeutic drugs, has also shown a remarkable enhancement in glycolysis with the increase of blood pressure at a low dose.…”

Pilot Study of Whole-Body Hyperthermia Combined with Chemotherapy in Patients with Metastasised Pretreated Progressive Breast, Ovarian, and Colorectal Carcinomas

“…According to the procedure of sCMT we induced high levels of hyperglycaemias to augment lactatacidosis in blood and tumour tissue [8]. Preclinical studies have shown that an acidic environment enhances heat-induced apoptosis [24] and that hyperglycaemia induced lactatacidosis combined with hyperthermia resulted in extensive tumour-growth inhibition [25].…”