The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of p...The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of proliferating (P) cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after the administration of pimonidazole followed by TPZ treatment or MTH. Twenty-four hours later, assessment of the responses of Q and total (= P + Q) cells were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q cells than total cells. Post-irradiation MTH more remarkably repressed the decrease in radio-sensitivity in the Q cell than the total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. On the other hand, in pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity due to delayed assay much more efficiently than MTH, whereas no radio-sensitizing effect was produced. Not only through suppressing the recovery from radiation-induced damage but also through radio-sensitizing effect, post-irradiation TPZ administration is very useful for repressing the increase in the difference in radio-sensitivity due to the delayed assay not only between total and Q tumor cells but also between the pimonidazole-unlabeled and the whole cell fractions within the total and Q tumor cells.展开更多
Systems describing the dynamics of proliferative and quiescent cells are commonly used as computational models, for instance for tumor growth and hematopoiesis.Focusing on the very earliest stages of hematopoiesis, st...Systems describing the dynamics of proliferative and quiescent cells are commonly used as computational models, for instance for tumor growth and hematopoiesis.Focusing on the very earliest stages of hematopoiesis, stem cells and early progenitors, the authors introduce a new method, based on an energy/Lyapunov functional to analyze the long time behavior of solutions. Compared to existing works, the method in this paper has the advantage that it can be extended to more complex situations. The authors treat a system with space variable and diffusion, and then adapt the energy functional to models with three equations.展开更多
Long-term quiescence or dormancy is a fundamental feature of cancer stem cells(CSCs)that are genetically identical to the malignant clone but constitute the only cells with tumor propagation potential within the overa...Long-term quiescence or dormancy is a fundamental feature of cancer stem cells(CSCs)that are genetically identical to the malignant clone but constitute the only cells with tumor propagation potential within the overall tumor population.These quiescent cells show significant resistance to radiation and antiproliferative chemotherapy due to distinctive properties that seem to be related to their stem cell-like character.Hence,successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells,but also the CSCs.Using serum-starved KG1a cell line as an experimental model system of quiescent leukemic cells(QLCs),the present study demonstrates that QLCs exposed to low concentrations of curcumin show high proliferative potential.Furthermore,when subjected to a combination therapy consisting of low concentrations of curcumin and 5-fluorouracil(5-FU),the QLCs displayed a high kill with an increase in the levels of nitric oxide(NO)and reactive oxygen species.These results were further consolidated with the observation of high caspase-3 activity in cells subjected to the combination therapy.This may suggest that low concentrations of curcumin stimulate the QLCs to become mitotically active,thereby sensitizing them to killing by the antimitotic drug,5-FU.展开更多
文摘The aim in this study is to examine the effect of tirapazamine (TPZ) and mild temperature hyperthermia (MTH) on the repair of radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells. Labeling of proliferating (P) cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after the administration of pimonidazole followed by TPZ treatment or MTH. Twenty-four hours later, assessment of the responses of Q and total (= P + Q) cells were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q cells than total cells. Post-irradiation MTH more remarkably repressed the decrease in radio-sensitivity in the Q cell than the total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. On the other hand, in pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity due to delayed assay much more efficiently than MTH, whereas no radio-sensitizing effect was produced. Not only through suppressing the recovery from radiation-induced damage but also through radio-sensitizing effect, post-irradiation TPZ administration is very useful for repressing the increase in the difference in radio-sensitivity due to the delayed assay not only between total and Q tumor cells but also between the pimonidazole-unlabeled and the whole cell fractions within the total and Q tumor cells.
基金supported by the European Research Council(ERC) under the European Union’s Horizon 2020 Research and Innovation Programme(No.740623)
文摘Systems describing the dynamics of proliferative and quiescent cells are commonly used as computational models, for instance for tumor growth and hematopoiesis.Focusing on the very earliest stages of hematopoiesis, stem cells and early progenitors, the authors introduce a new method, based on an energy/Lyapunov functional to analyze the long time behavior of solutions. Compared to existing works, the method in this paper has the advantage that it can be extended to more complex situations. The authors treat a system with space variable and diffusion, and then adapt the energy functional to models with three equations.
文摘Long-term quiescence or dormancy is a fundamental feature of cancer stem cells(CSCs)that are genetically identical to the malignant clone but constitute the only cells with tumor propagation potential within the overall tumor population.These quiescent cells show significant resistance to radiation and antiproliferative chemotherapy due to distinctive properties that seem to be related to their stem cell-like character.Hence,successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells,but also the CSCs.Using serum-starved KG1a cell line as an experimental model system of quiescent leukemic cells(QLCs),the present study demonstrates that QLCs exposed to low concentrations of curcumin show high proliferative potential.Furthermore,when subjected to a combination therapy consisting of low concentrations of curcumin and 5-fluorouracil(5-FU),the QLCs displayed a high kill with an increase in the levels of nitric oxide(NO)and reactive oxygen species.These results were further consolidated with the observation of high caspase-3 activity in cells subjected to the combination therapy.This may suggest that low concentrations of curcumin stimulate the QLCs to become mitotically active,thereby sensitizing them to killing by the antimitotic drug,5-FU.
