It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

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Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro.

It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5 degrees C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5 degrees C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T(0) (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37 degrees C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T(0) at 37 degrees C to the T(0) at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.

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PubMedDate not supplied

For the clinical application of thermochemotherapy given at mild temperatures.

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.

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Effect of thermochemotherapy on the development of spontaneous lung metastases.

Effect of local hyperthermia given alone or in combination with cyclophosphamide and/or hyperglycaemia on the development of lung metastasis was studied using a non-immunogenic mouse fibrosarcoma, FSa-II. Incidence of lung metastasis was dependent upon the tumour size, and was increased when tumour-bearing mice were restrained in animal holders which were used for heat-treatment of animal tumours. The frequency of the metastatic spread was decreased following local hyperthermia at 41.5 degrees and 45.5 degrees C when compared to that following sham treatment. This decrease was independent of the heat dose. Similar reduction in the incidence of metastasis was observed after hyperthermia given following glucose administration. The administration of cyclophosphamide effectively inhibited the development of lung metastasis. However, the magnitude of the inhibition was identical to that following hyperthermia alone. In conclusion, hyperthermia given alone, or in combination with hyperglycaemia or cyclophosphamide, inhibited the development of lung metastasis.

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PubMedDate not supplied

The effect of bleomycin administered in combination with hyperthermia on a C3H mouse fibrosarcoma.

The effect of bleomycin (BLM) on a murine fibrosarcoma, FSa-II, was investigated at elevated temperatures. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Single-cell suspensions of the tumour were transplanted into the murine foot. Tumours with an average diameter of 4 mm were treated in a water bath where a desired temperature was maintained. Some animal groups received an intraperitoneal injection of glucose 60 min before hyperthermia to reduce tumour tissue pH. Hyperthermia was given for 60 min at 41.5 degrees C, 30 min at 43.5 degrees C, or 60 min at 43.5 degrees C, and tumour growth (TG) time to reach 1000 mm3 was studied. BLM treatment at 41.5 degrees C for 60 min prolonged the TG time compared to BLM treatment at a room temperature. The identical prolongation was observed following BLM treatment given at 43.5 degrees C for 30 min, although the growth prolongation was greater following BLM treatment given at 43.5 degrees C for 60 min than the other two treatments. This greater prolongation is probably attributable to an additive effect; namely hyperthermia of 43.5 degrees C for 60 min induces substantial lethal damage by itself while the other two heat treatments do not induce significant damage. It is interesting to note that this kind of enhancement was observed at a low temperature of 41.5 degrees C. A glucose injection before BLM and hyperthermia treatments further enhanced tumour response. These observations agree with our previous observations following in vitro treatments of the same tumour cells, and indicate that BLM is a good drug to be combined with hyperthermia.

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PubMedDate not supplied

The effect of preirradiated tumour bed on the response of a murine fibrosarcoma to elevated temperatures.

The effect of pretransplantation irradiation of tumour beds (tumour bed effect or TBE) on the response of tumours to elevated temperatures and on the kinetics of thermo-tolerance was studied. Animal tumours were early generation isotransplants of a fibro-sarcoma, FSa-II in C3Hf/Sed mice. The tumour bed or murine foot was irradiated with 0.8 or 16 Gy in air, and tumour cell suspensions were transplanted 1-35 days thereafter. Hyperthermia of various durations was given in a 45.5 degrees C water bath when tumours reached an average diameter of 6 mm (110 mm3), and the tumour growth (TG) time to reach 500 mm3 was obtained. Dose-response curves between the TG time and the treatment time were less steep for tumours in preirradiated tumour beds than for tumours in non-irradiated tumour beds, indicating that the tumours in preirradiated tumour beds were more resistant to hyperthermia compared to the tumours in normal tumour beds. This resistance appeared to increase with increasing preirradiation dose. Thermotolerance was equally developed in tumours in normal and preirradiated tumour beds. The time required to develop the maximum thermotolerance was identical for both tumours. This indicated that the TBE has no effect on the kinetics of thermotolerance. The implication of these results in clinical trials may be that the tumour which recurred after radiotherapy may not be a good candidate for hyperthermia.

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