Acidification-induced sensitization to thermoradiotherapy in breast cancer

Hyperthermia is an extensively studied cytotoxic agent, with strong radio- and chemosensitizing potential. Recent positive clinical trials combining superficial or deep heating techniques with radiation therapy strongly support a role for hyperthermia as an adjuvant to radiation. Many in vitro and in vivo studies have shown that acute extracellular acidification will compromise fundamental protective cellular responses and enhance tumor response to hyperthermia and chemotherapy.

Breast cancers, like most other tumors, exhibit elevated levels of lactate production that provides a basis for selective acidification. A phase I/II clinical trial is underway to test the hypothesis that hyperglycemia-induced acute acidification will sensitize carcinoma of the breast to thermoradiotherapy. Six patients consented to fast for at least 4 h and ingest oral glucose (2 g/kg, 0.44 g/ml) 1.5 h before each hyperthermia treatment (HT) during a course of thermoradiotherapy. Hyperglycemia reduced tumor pH_e before the first hyperthermia session by 0.10 ± 0.04 pH unit (-0.29 to +0.08) from 7.12 ± 0.11 (6.65-7.52); and during the third week of treatment hyperglycemia reduced tumor pH_e in five patients by 0.01 ± 0.04 pH unit (-0.06 to +0.1). The three patients with a CR (60%) exhibited tumor acidification during both sessions, in contrast to the two patients with a PR (40%) who exhibited tumor acidification only during one session. Tumor acidification may indicate tumor response.

Human tumor cells adapted to growth at pH_e 6.7 do not show thermosensitization until pH_e is below 6.3 (pH_i < 6.45). Combining an inhibitor of respiration such as MIBG with hyperglycemia blocks mitochondrial respiration and increases lactate production. Thus, tumor oxygenation occurs coincidentally with acute acidification.

Rats bearing the R3230 Ac rat mammary adenocarcinoma were administered 1 g/kg glucose ip, and/or 20 mg/kg MIBG ip. The median pO₂ for glucose plus MIBG was increased from 5.3 to 13.8 mmHg. A single ip injection of glucose or MIBG in rats fasted for 24 h before irradiation did not show an increase in tumor growth delay compared with 5 Gy radiation alone. However, combined treatment with glucose plus MIBG significantly inhibited tumor growth delay. Radiation therapy and glucose plus MIBG was more than additive. These results support our hypothesis that hyperglycemia plus an inhibitor of respiration will sensitize tumors to radiation by oxygenation, in addition to enhanced hyperthermia sensitization by acute acidification.

Supported in part by USPHS grant CA59960.