Hyperthermia and Cancer

SummaryThe most prominent cellular changes in heat-shock response are induction of HSPs synthesis and reorganisation of cytoskeleton. Vincristine was used as a tool to evaluate the integrity of microtubules in 9L rat brain tumour cells recovering from heat-shock treatment. Cells treated at 45°C for 15 min and recovered under normal growing condition became resistant to vincristine-inflicted cytotoxicity and microtubule destruction. Among all HSPs, the level of HSP70 and the degree of vincristine resistance are best correlated. HSP70and tubulin were found to be associated with each other as they were co-immunoprecipitated by either anti-HSP70 or anti-p-tubulin monoclonal antibody. The current studies establish for the first time that HSP70can complex with tubulin in cells and this association may stabilise the organisation of microtubules thus protect the heat-treated cells from vincristine damage. These findings are noteworthy in combining hyperthermia and chemotherapy in the management of malignant diseases.Heat-shock proteins (HSPs) are a small set of proteins induced in cells subjected to supraoptimal temperature and other related physiological stresses (Lindquist & Craig, 1988;Schlesinger, 1990;Schlesinger et al., 1990; Morimoto et al., 1990). The synthesis of HSPs is suggested to be related to the development of thermotolerance in cells that survived the initial heat-treatment (Li & Mak, 1985;Hahn & Li, 1990;Black & Subjeck, 1990). The HSPs are highly conservative and usually termed by their apparent molecular weights. Three classes of major HSPs, i.e., HSPl10, 90 and 70 are commonly detected in mammalian cells (Lindquist & Craig, 1988). HSP70 exists as a family in most organisms and has been the most extensively studied. In rodent cells, this family consists of two closely related proteins (>80% homology at the amino acid level) which have been known as the constitutive form of HSP70 (also known as HSC70, designated as HSP72 hereafter because of its slightly higher molecular weight) and the inducible form of HSP70 (designated as the HSP70 hereafter) (Hightower & White, 1981;Lee et al., 1991). HSP72 is slightly heat inducible, constitutively expressed and found at higher levels in growing cells than in resting cells (Pelham, 1986). This protein was found to be multifunctional. It functions as clathrin uncoating ATPase (Chappell et al., 1986;Deluca-Flaherty et al., 1990) and as molecular chaperone that binds to nascent polypeptides and maintains them in unfolded states, to facilitate their intracellular translocation (Deshaies et al., 1988;Chirico et al., 1988) and/or to accelerate their proper folding and oligomerisation (Beckmann et al., 1990;Pelham, 1990). Recently, HSP72 has been shown to be involved the in vivo assembly of microtubules (Gupta, 1990). On the other hand, HSP70 is highly heat inducible and hardly detectable under normal conditions. Its function is suggested to be similar to that of HSP72 because of the high degree of homology between these two proteins (Lindquist & Craig, 1988). In additi...

Section: Discussionmentioning

confidence: 99%

Induction of HSP70 is associated with vincristine resistance in heat-shocked 9L rat brain tumour cells

Lee¹,

Lin²,

Chen³

et al. 1992

“…from 0.57 to 1.35 Gy, the Dq-values from 0.36 to The response to hyperthermic treatment of 2.68 Gy and the n-values from 1.4 to 78. The experimental and human tumours has been survival curve parameters for the present two slowly extensively studied lately (Hahn, 1982;Storm, 1983). growing melanoma xenografts (Table II) (Kim et al, 1975;Gerweck, 1977).…”

Section: Resultsmentioning

confidence: 99%

Radiation and heat sensitivity of cells from two slowly growing human melanoma xenografts

Rofstad¹,

Wahl²,

Brustad³

1984

“…Experimental investigations including studies of transplantable tumours in small rodents and spontaneous tumours in pet animals have indicated that hyperthermia may become a useful modality for treatment of human cancer (Hahn, 1982;Storm, 1983). Heat is cytotoxic to tumour cells, potentiates the effects of ionising radiation and enhances the uptake and cytotoxicity of some chemotherapeutic agents.…”

mentioning

confidence: 99%

“…The thermobiology of cells in culture has been studied extensively, and important information relevant to hyperthermic treatment of cancer has been obtained (Hahn, 1982;Storm, 1983). First, heat survival curves in vitro show the same shape as X-ray survival curves, i.e.…”

mentioning

confidence: 99%

Heat sensitivity and thermotolerance in vitro of human breast carcinoma, malignant melanoma and squamous cell carcinoma of the head and neck

Rofstad

1990

Summary Heat sensitivity and the development of thermotolerance of cells isolated directly from surgical specimens of human breast carcinoma, malignant melanoma and squamous cell carcinoma of the head and neck were studied in vitro using the Courtenay soft agar colony assay. The plating efficiency of some of the tumours was sufficiently high (0.3-20.4%) for survival curves covering up to two to three decades to be established. Experiments repeated with cells stored in liquid nitrogen showed that the survival assay gave highly reproducible results. Heat sensitivity of thermotolerant cells was studied by giving cells a conditioning heat treatment of 43.5°C for 60 min and, after incubation at 37C for 24 h, second graded heat treatments at 43.5'C. Significant differences in heat sensitivity and development of thermotolerance between the three tumour types were not found. However, the heat sensitivity, whether the cells were thermotolerant or not, differed considerably among individual tumours of each histological category. Do at 43.5°C was found to be in the ranges of 23 -59 min (breast carcinoma), 20 -63 min (malignant melanoma) and 20-57 min (squamous cell carcinoma) for single-heated cells and 105-476 min (breast carcinoma), 102-455 min (malignant melanoma) and 87-400 min (squamous cell carcinoma) for thermotolerant cells. The heat sensitivity of cells made thermotolerant showed no significant correlation to the surviving fraction after the conditioning heat treatment. The study indicated that histological category is a poor parameter for assessment of clinical heat responsiveness of tumours. Breast carcinoma, malignant melanoma and squamous cell carcinoma are probably, from a thermobiological point of view, equally good candidates for clinical trials aimed at studying the potential usefulness of hyperthermia as an adjunct to radiation therapy and/or chemotherapy. The large differences in heat sensitivity and development of thermotolerance observed among individual tumours, irrespective of histological origin, suggested that an in vitro predictive assay for heat responsiveness would be very useful for stratification purposes in such clinical trials.