| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 84 === The mechanisms of chemoresistance of human transitional cell
carcinoma (TCC) are far to be understood. Further study is
necessary to effectively circumvent it. In results, all the
benign epithelia were mdr-1 mRNA positive and 70% of tumors and
only 20% of TCC cell lines were mdr-1 positive. The possible
explanation is that rapidly growing tumor cells have to drop
out energy-dependent mechanisms to afford the requirement of
cell growth and replication. Once tumor cells meet an
undesirable environment with toxic substance, energy-dependent
detoxification appratus emerges to survive. The P-glycoprotein(
P-gp) expression did not correlate with the response of either
intravesical or systemic chemotherapy in our results. mdr-1
expression seemed not responsible for the primary resistance of
TCC. However, it appeared to be responsible for part of the
secondary resistance from the cell line model. Verapamil,
tamoxifen and megace can reverse the secondary doxorubicin
resistance in TCC cells. No reversal was seen in the
resistance of the parental sensitive cell lines. The latter
could be seen in the sensitive TCC cells treated with
methotrexate, vinblastine and cisplatin in systemic model or
with mitomycin-C and thiotepa in intravesical model. Unlike
verapamil by which P-glycoprotein was inhibited directly,
tamoxifen and megace reversed the doxorubicin resistance
through other pathways, which need further study. The sequence
of giving chemotherapeutic agents and modulators appeared to
influence the outcome of growth inhibition. Less cytotoxic
effects were noted if doxorubicin was given after several hours
of modulator treatment. More inhibition effects were seen if
they were given in a reversed sequence. Protein kinase C
involvement in addition to cell cycle regulation may be
responsible for the mechanisms involved. Other pathways may
contribute to this effect and conclusions should not be made
until more data are available.
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