Masashi Tsumura

Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia.

The combined effect of granulocyte-colony stimulating factor (GCSF) and hyperthermia in the treatment of experimental tumours was studied to examine the possible involvement of activated granulocytes in the antitumour effect of hyperthermia. Two weeks after transplantation of SCC VII cells (1 x 105) into the instep of the left leg of C3H/HeJ male mice, the mice were given subcutaneous injections of GCSF (0.2mg/kg) for 4 days. On day 4, hyperthermia was applied locally at 43 C for 40min. Hyperthermia inhibited the tumour growth, and this effect was enhanced by pre-treating the animals with GCSF. The numbers of circulating neutrophils in control and GCSF-treated mice were 2728 +/- 517/mul and 3124 +/- 194/mul, respectively ( p = 0.53). Hyperthermia increased the number of neutrophils to 4409 +/- 700/mul ( p < 0.05). Hyperthermia combined with GCSF significantly increased the number of netrophils to 5479 +/- 691/mul ( p < 0.01). Chemiluminescence analysis using L-012 revealed that GCSF enhanced the generation of reactive oxygen species by about 10-fold. Glutathione contents in tumours 24h after hyperthermia decreased by about 50% in both the hyperthermia groups with or without GCSF, as compared to those in the control. The GCSF-enhanced anti-tumour activity of hyperthermia was markedly inhibited by administration of a long-acting superoxide dismutase derivative (SM-SOD). These results suggest that GCSF activates the ability to generate active oxygen species by neutrophils and, thereby, enhances the anti-tumour effect of hyperthermia.

Effect of lactic acid in tumours on antitumour activity of hyperthermia

The change of lactic acid concentration in the tumour after intraperitoneal administration of 5 g/kg glucose, and the effect of the lactic acid concentration on antitumour activity of hyperthermia were studied in an experimental murine tumour. The lactic acid concentration in SCC VII tumours transplanted into the legs of C3H/HeJ male mice was measured by gas chromatography. Local hyperthermic treatment to the tumour was performed with a water bath at 43 degrees C for 40 min. Antitumour effects were evaluated by measuring tumour volume doubling time (DT) as an index. The mean concentration of lactic acid in the tumour was 10.4 mumol/g in the no-treatment group. The lactic acid concentration gradually increased after glucose administration, reaching a significantly high concentration of 20.0 mumol/g at 90 min later. The DTs in the no-treatment group and hyperthermia alone group were 2.4 and 3.7 days respectively. The DTs in the glucose administration groups shortly before, 30 and 60 min before the hyperthermia were 3.6, 3.6 and 5.6 days respectively. The DT in the 60 min group was significantly extended (p < 0.0001). Hyperthermia during the period of increased lactic acid concentration significantly prolonged the DT of the tumour. These results clearly showed that an increase of lactic acid concentration in the tumour improved the effect of local hyperthermia.

Phase II study of concurrent chemoradiotherapy with use of uneven fractionation for the treatment of glioblastoma

BackgroundA phase II one-arm study was performed to evaluate the efficacy and safety of concurrent chemoradiotherapy with the use of uneven fractionation in glioblastoma patients.MethodsA total of 19 glioblastoma patients underwent concurrent chemoradiotherapy with the use of uneven fractionation. Vincristine (VCR) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) were administered on day 1 and day 2, respectively. Irradiation at a dose of 3 Gy was administered on days 3 and 4, and at a dose of 1.5 Gy from day 5 on. The treatment was repeated at 10 day intervals. The total radiation dose was 57 Gy.ResultsAll 19 patients received full dose irradiation. However, 8 patients required treatment interruption, and 2 patients required decreases in drug dosages due to the effects of acute toxicity such as, myelosuppression, liver function disorder and skin toxicity. The treatment responses were recorded as CR in 5, PR in 1, and NC in 10 patients. The remaining three patients received total removal of the enhancing area on CT or MRI. The 1 year and 2 year survival rates were 73% and 23%, respectively. The median survival times of this study and the historical controls were 16 months and 15 months, respectively.ConclusionThe concurrent chemoradiotherapy failed to prolong the survival of glioblastoma patients.