Selective protection of non-cancer cells by hypothermia.
BACKGROUND
A serious limitation in cancer treatments is insufficient selectivity of drugs for cancer cells. We have previously demonstrated that, in contrast to p53-deficient cells, cells with wild-type p53 undergo a reversible cell cycle arrest when incubated at 28 degrees C instead of 37 degrees C. Since most of the human tumors are p53-deficient, it suggests that hypothermia may selectively protect normal cells from cytotoxic treatments that primarily target proliferating cells.


METHODS
We have examined the effect of hypothermia on the survival of wild-type and p53-deficient cells exposed to the anti-tumor drug 5-fluorouracil and compared BrdU incorporation at 28 degrees C and 37 degrees C of normal and tumor cells.


RESULTS
p53 wild-type fibroblasts, in contrast to p53-deficient cells, survive much higher doses of 5-fluorouracil when incubated at 28 degrees C than at 37 degrees C. Among tumor cells, the loss of the p53 function coincides with the inability to arrest cell cycle progression at low temperature and with increased sensitivity to prolonged hypothermia as a single modality.


CONCLUSIONS
Hypothermia protects normal cells from cytotoxic treatments and may improve the therapeutic index of chemotherapy by mechanisms based on the differences in cell cycle regulation between normal and tumor cells.
Matijasevic
Zdenka
Z
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, M4 01655-0126, USA. zdenka.matijasevic@umassmed.edu
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005472:Fluorouracil / Q000009:adverse effects* / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D001973:Bromodeoxyuridine; D005472:Fluorouracil