The aim of this study was to understand the role of
tumor progression in the growth properties of
tumor cells and their susceptibility to the cytotoxicity of chemotherapeutic drugs. A murine transplantable
T cell lymphoma of spontaneous origin, designated as Dalton's
lymphoma, was used as a model
tumor for this investigation.
Tumor cells were harvested from the early (5 days after
tumor transplantation) and late
tumor-bearing stages (17 days after
tumor transplantation), with or without in-vivo administration of the chemotherapeutic drugs,
cisplatin or
doxorubicin.
Tumor cells harvested at the late
tumor-bearing stages showed a higher proliferative ability in vitro.
Tumor progression was found to be associated with a decline in the
tumor cytotoxicity of the chemotherapeutic drugs. Similar results were also obtained when
tumor cells were cultured at low (10(5) cells/ml) and high (10(9) cells/ml) cell densities in vitro in medium alone or in one containing the chemotherapeutic drugs. An increase in the expression of
heat shock protein (Hsp70),
vascular endothelial growth factor,
interleukin-2 receptor and
interleukin-2 proteins along with an inhibition in the expression of
caspase-activated DNase and p53
proteins was observed during the late
tumor-bearing stage and also in the Dalton's
lymphoma cells when cultured in vitro at a higher cell density. The ascitic fluid obtained from the late
tumor-bearing stage and the culture supernatant of
tumor cells incubated in vitro at high cell density showed high levels of cell growth-regulating
cytokines:
interleukin-1,
interleukin-2,
interferon-gamma,
vascular endothelial growth factor,
tumor growth factor-beta and
interleukin-10. In-vivo administration of
cisplatin in
tumor-bearing mice at the late
tumor-bearing stage did not alter the level of these
cytokines in the ascitic fluid. In view of the results of this investigation, it is suggested that under high cellular density-associated environmental conditions the
tumor cells alter their growth properties depending on an alteration in the expression of cell growth and apoptosis-regulating
proteins.
Tumor cells, thus, switch to a high level of proliferation, which renders them resistant to the cytotoxicity of chemotherapeutic drugs.