Effects of hyperthermia on the metabolism of 5-fluorouracil in vitro.

The effects of hyperthermia (38-42 degrees C) on the metabolism of 5-fluorouracil (5-FU) were examined using Ehrlich tumour cells (E-cells) and Sarcoma-180 cells (S-180 cells) in vitro. A temperature-dependent elevation of the intracellular concentration of 5-FU was observed in both types of tumour cell after incubation with 5-FU. The levels of 5-fluorouridine (FUR) and 5-fluoro-2'-deoxyuridine (FdUR), which are active metabolites of 5-FU, increased significantly after treatment of cells with 5-FU and hyperthermia. The highest concentrations of these active metabolites were found when the cells were incubated at 39 degrees C. The levels of alpha-fluoro-beta-ureido-propionic acid (FUPA) and F-beta-alanine, which are inactive catabolic metabolites of 5-FU, also increased when the cells were incubated at 39 degrees C. The percentage inhibition of thymidilate synthetase (TS) activity remained high (about 60-70%) at 39 degrees C for 240 min. These results suggest that the optimal temperature for potentiating the intracellular metabolism of 5-FU, in terms of both activation and inactivation, is 39 degrees C in vitro.

Attempt to induce total-body hyperthermia by whole-abdominal hyperthermia using a radiofrequency capacitive-heating system: an experimental study in dogs.

The effects of whole-abdominal hyperthermia (WAH), using an 8 MHz radiofrequency capacitive-heating system, on the intraperitoneal and extraperitoneal distribution of heat and on the functions of visceral organs were studied. Eight female mongrel dogs were divided into two groups. Five were infused and three were not infused intraperitoneally with physiological saline. The mean increase in systemic temperature during WAH was 6.4 degrees C for the saline-infused group and 5.1 degrees C for the non-infused group. The systemic temperature reached 40 degrees C about 50 min after the start of heating in four of five animals in the saline-infused group; three of the four animals died, and in these the maximum temperature of the liver exceeded 43.5 degrees C. The infusion of saline into the peritoneal cavity may facilitate the elevation of systemic temperature. The effects on the liver of WAH were very marked, as analysed by biochemical and histological techniques. Visceral organs tolerated heating to less than 43 degrees C by WAH alone. It appears that elevation of the systemic temperature to 40.5 degrees C or more can be safely achieved under conditions where the temperature in the peritoneal cavity is kept below 43.5 degrees C during WAH.

[Hepatic arterial chemotherapy combined with hyperthermia or arterial embolization in unresectable liver tumor].

Fifty-four patients with unresectable malignant liver tumors (14 of hepatocellular carcinoma, 40 of metastasis to the liver from gastric or colo-rectal cancer) were treated with intra-hepato-arterial (IHA) injections of cis-diamminedichloroplatinum (II) (CDDP) plus 5-fluorouracil (5-FU). In 32 of the patients, the liver tumors were detected synchronously with the diagnosis of the primary cancers, which were resected palliatively. Therapeutic schedules consisted of bolus injections of CDDP (50 mg/body/week) and 5-FU (250 mg/body/day) [Regimen I], and CDDP (50 mg/body/10-14 days) and 5-FU (100 mg/body/day) [Regimen II]. In 48 patients treated with IHA chemotherapy only, a partial response (PR) was obtained in 6 of 14 (43%) evaluable patients for Regimen I and in 11 of 30 (37%) patients for Regimen II. The dose-limiting factor for treatment with CDDP was bone marrow toxicity, but this toxicity was remarkably alleviated in Regimen II without any decrease in antitumor effectiveness. In 13 patients, other modalities, such as total-body hyperthermia (4 patients), radiofrequency capacitive local hyperthermia (5), and temporary arterial embolization (4), were combined with IHA chemotherapy. PR was obtained in 7 of 13 (54%) patients with the combined therapy. This combined therapy was efficacious in 7 patients in whom no desired results were obtained by IHA chemotherapy only. The survival rate was 50% at 12 months. IHA chemotherapy with CDDP plus 5-FU, especially when according to Regimen II, appears to be a strongly recommended strategy for treatment of unresected primary or metastatic liver tumor. Further, addition of the hyperthermia or the arterial embolization might enhance the antitumor effect of IHA chemotherapy.

[Clinical results and problems of total-body thermochemotherapy].

The clinical results and problems of extracorporeally-induced total-body thermochemotherapy (TBHT) for recurrent cancer are presented. A total of 127 hyperthermic treatments were performed in 45 patients who had undergone unsuccessful conventional systemic anticancer chemotherapy. Partial response was observed in 11 of 34 evaluable patients (32%). In analysing the anticancer effects of TBHT according to cancer site, a high efficacy was observed in patients with their main tumor in the lung, liver and lymph nodes. The anticancer effects were most enhanced when TBHT was performed in combination with cisplatin and 5-fluorouracil. In order to augment the anticancer effects of TBHT, the choice of combined agents and administration timing are important. A useful method for determining the thermochemosensitivity of individual cancer cells to agents selected for drug treatment is the human tumor clonogenic assay. Furthermore, the usefulness of angiotensin II-induced hypertensive chemotherapy during TBHT for augmenting selective drug delivery to cancer tissue is stressed.