Anti-Metastatic Benefits Produced by Hyperthermia and a CCL3 Derivative

Abstract

Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, we show in this article that intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia not only induces tumor growth inhibition at the treated site but also inhibits metastasis. Colon26 adenocarcinoma cells (1 × 105 cells/mouse) were grafted subcutaneously into the right hind leg of syngeneic BALB/c mice and after nine days, when tumor size reached ~11 mm in diameter, the local tumor mass was exposed to high-frequency waves, by which intratumoral temperature was maintained at 42 °C for 30 min. Mice received the CCL3 variant named eMIP (2 μg/mouse/day) intravenously for five consecutive days starting one day after heat treatment. We found that tumor growth in eMIP recipients after hyperthermia was inhibited markedly but no effect was seen in animals treated with either hyperthermia or eMIP alone. Furthermore, the number of lung metastases evaluated at 18 days after hyperthermia treatment was dramatically reduced in animals receiving the combination therapy compared with all other controls. These results encourage future clinical application of this combination therapy.

Hyperthermia

“…The presence of signs and symptoms related to hyperthermia syndrome, such as extrapyramidal symptoms characteristic of neuroleptic malignant syndrome, and the absence of signs and symptoms more commonly related to the infection related fevers, are also considered in making the diagnosis. (7). Hyperthermia is an adjuvant local anticancer treatment using temperatures exceeding the physiologically optimal level, typically 40-43 degree centigrade for approximately one hour.…”

Hyperthermia-Based Anti-Cancer Treatments

“…Mei et al investigated the impact of temperature (37–42 °C), sequence and time interval (0 up to 4 h) for ionizing radiation combined with hyperthermia on different HPV-positive and HPV-negative cervical cancer cell lines, demonstrating that shorter time intervals were associated with more unrepaired DNA damage and more tumour cell kill, especially at higher temperatures [ 6 ]. Hyperthermia at 42 °C was also demonstrated to have a marked potential in inducing an immunes response in an in vivo mouse model of colon adenocarcinoma, where intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia treatment not only induced significant tumour growth inhibition but also inhibited metastasis [ 7 ]. Hader et al investigated the impact of the heating method on changes in the immune phenotype of tumour cells, comparing the effect of warm-water bath versus 2.45 GHz microwave heating on cell death, the release of HSP70, and the expression of immune checkpoint molecules (ICMs) on breast cancer cells.…”