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1.
Jianguo Ma Marc Maliepaard Herman J. Kolker Jaap Verweij Jan H. M. Schellens 《Cancer chemotherapy and pharmacology》1997,41(3):186-192
The parental IGROV-1 human ovarian adenocarcinoma cell line was intermittently exposed to increasing concentrations of cisplatin
to obtain resistant sublines. A stable resistant subline with a resistance factor of 8.4 had been developed after 9 months
and 28 passages, which was denoted IGROVCDDP. A high correlation coefficient of 0.97 was found between the log cell survival and the DNA-adduct peak level during the
process of resistance development. IGROVCDDP was strongly cross-resistant to carboplatin and doxorubicin and moderately cross-resistant to etoposide, docetaxel, and topotecan.
Only minor resistance against 5-fluorouracil was observed, whereas IGROVCDDP was not cross-resistant to methotrexate. Intracellular accumulation of cisplatin was 65% lower in IGROVCDDP as compared with parental IGROV-1 at 37 °C under normal conditions. Coincubation of cisplatin with the Na+/K+-ATPase inhibitor ouabain resulted in a more pronounced decrease in platinum accumulation in IGROV-1 (44% decrease) than in
IGROVCDDP (26% decrease). Under energy-depleting conditions the accumulation of cisplatin in the parental cell line was approximately
60% lower than that observed under normal (energy [i.e., ATP] rich) culture conditions. In contrast, the accumulation in IGROVCDDP was not affected by ATP-depletion. There appeared to be no significant difference between the intracellular accumulation
of platinum in the resistant and sensitive cells under conditions of energy deprivation or when the uptake was studied at
0 °C. In conclusion, abrogation of energy-dependent accumulation in IGROVCDDP seems to be a major mechanism of resistance to cisplatin in this cell line.
Received: 21 January 1997 / Accepted: 22 July 1997 相似文献
2.
J. Ma M. Maliepaard K. Nooter W. J. Loos H. J. Kolker J. Verweij G. Stoter J. H. Schellens 《British journal of cancer》1998,77(10):1645-1652
In order to unravel possible mechanisms of clinical resistance to topoisomerase I inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROV(T100r), by stepwise increased exposure to topotecan (TPT). The IGROV(T100r) cell line was 29-fold resistant to TPT and strongly cross-resistant to SN-38 (51-fold). However, the IGROV(T100r) showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase I protein levels and catalytic activity as well as topoisomerase I cleavable complex stabilization by CPT in the IGROV-1 and IGROV(T100r) cell lines were observed, indicating that resistance in the IGROV(T100r) cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROV(T100r) cell line to TPT and SN-38 was accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROV(T100r) cell line increased under these energy-deprived conditions. The efflux of TPT at 37 degrees C was very rapid in the IGROV-1 as well as the IGROV(T100r) cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROV(T100r) cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROV(T100r) cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase I drugs. 相似文献
3.
Erlichman C Boerner SA Hallgren CG Spieker R Wang XY James CD Scheffer GL Maliepaard M Ross DD Bible KC Kaufmann SH 《Cancer research》2001,61(2):739-748
Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents. 相似文献
4.
H Ulukan M T Muller P W Swaan 《International journal of cancer. Journal international du cancer》2001,94(2):200-207
To better understand the increased sensitivity of proliferating intestinal epithelial cells to topoisomerase I (topo I) poisons, we examined differentiation of a human intestinal cell line (Caco-2) in the presence of camptothecin (CPT) and its analogs irinotecan (CPT-11) and topotecan (TPT). The prodrug CPT-11 exerts its antitumor activity after transformation to SN-38. We show that cleavable complex formation in vivo (on genomic DNA) induced by CPT or SN-38 is 4- to 7-fold reduced in fully differentiated cells relative to undifferentiated cells. TPT-induced cleavable complexes, however, are reduced by 30-fold. In contrast, CPT-11-driven cleavable complexes did not change during cell differentiation. In general, cytotoxicity closely paralleled cleavable complex formation, as attested to by the four- to 6-fold decrease in cytotoxicity in fully differentiated cells treated with CPT and SN-38 compared with proliferating cells. Topo I activity and polypeptide levels decreased 4-fold over the course of differentiation. This reduction occurs as Caco-2 cells approach G(1) and simultaneously differentiate. In contrast, human diploid fibroblasts do not show a reduction in topo I when entering G(1); therefore, topo I downregulation is a differentiation-specific event in the Caco-2 cell line. Cleavable complex formation and cytotoxicity induced by CPT and SN-38 correlate with topo I level and activity in cells at different stages in their differentiation. Thus, high target levels correspond closely with drug sensitivity and since proliferating cells contain larger amounts of topo I, we conclude that epithelial crypt cells probably succumb to chemotherapy involving topo I poisons. 相似文献
5.
Purpose: We have previously shown that neuroblastoma cell lines established from patients after intensive chemotherapy show sustained
resistance to various drugs and especially high resistance to etoposide (up to 51 times higher than a clinically achievable
level). To determine whether topoisomerase I inhibitors (topotecan and CPT-11) are effective against etoposide-resistant neuroblastomas,
we studied the response to topotecan and the active metabolite of CPT-11 (SN-38) in 19 cell lines with a spectrum of sensitivities
to etoposide. Materials and methods: The panel included cell lines established at diagnosis and after disease progression either during induction chemotherapy
or after myeloablative therapy supported with bone marrow transplantation. Cytotoxicities of topotecan, SN-38, and etoposide
were determined using a microplate digital image microscopy (DIMSCAN) assay with a 4-log dynamic range. Results: All six etoposide-resistant cell lines were resistant to topotecan and SN-38 (resistance defined as LC90 higher then clinically achievable levels for the drug). Significant cross-resistance by Pearson's correlation analysis (r ≥ 0.6) occurred between topotecan + etoposide, topotecan + SN-38, and etoposide + SN-38. Conclusions: Topotecan and CPT-11 do not have significant activity against most etoposide-resistant neuroblastoma cell lines and this
suggests that agents other than topoisomerase inhibitors should be explored for the treatment of recurrent neuroblastomas.
Received: 19 January 1999 / Accepted: 24 May 1999 相似文献
6.
Chikamori M Takigawa N Kiura K Tabata M Shibayama T Segawa Y Ueoka H Ohnoshi T Tanimoto M 《Anticancer research》2004,24(6):3911-3916
Irinotecan is one of the most active drugs used in the treatment of small cell lung cancer (SCLC). 7-Ethyl-10-hydroxy-camptothecin (SN-38) is an active metabolite of irinotecan. We established an SN-38-resistant subline (SBC-3/SN-38) by continuous exposure of SN-38 to a human SCLC cell line, SBC-3. Using the 3-[4, 5-dimethyl-thiazol-2-yl] 2, 5-diphenyltetrazolium bromide assay, we evaluated the cytotoxicity of 17 anticancer agents. The SBC-3/SN-38 cells were 73-fold more resistant than the parental SBC-3 cells to SN-38 and showed cross-resistance not only to topoisomerase (topo) I inhibitors (irinotecan and topotecan), but also to topo II inhibitors (adriamycin and etoposide), antimicrotubule agents (vincristine, vindesine, vinorelbine and docetaxel), alkylating agents (cyclophosphamide and ifosfamide), platinum (cisplatin and carboplatin) and antifolate (methotrexate). Interestingly, the resistant subline reserved the sensitivity to bleomycin and 5-fluorouracil. The SBC-3/SN-38 cells had decreased topo I and II activity compared to the parent cells. The SN-38-resistant cell line, SBC-3/SN-38, will be useful to elucidate the mechanism of action of the topo I inhibitors. 相似文献
7.
Sally Mullany Phyllis A. Svingen Scott H. Kaufmann Charles Erlichman 《Cancer chemotherapy and pharmacology》1998,42(5):391-399
Purpose: To determine the effect of combined treatment with 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan)
and 5-fluorouracil/folinic acid (5FU/FA) in vitro using HCT-8 human intestinal adenocarcinoma cells. Methods: Cell survival was examined using colony forming assays. Cell cycle distribution before and after treatment was assessed
by flow microfluorimetry. Levels of thymidylate synthase (TS) and topoisomerase I (topo I) in untreated and treated cells
were determined by immunoblotting. Changes in deoxynucleotide pools were examined by high-performance liquid chromatography.
Results: Clonogenic assays revealed that colony formation was decreased by 50% after a 24-h exposure to 8 ± 2 nM SN-38 or 12 ± 3 μM 5FU, the latter being assayed in the presence of 2 μM FA. When treatment with 5FU/FA was followed by SN-38, the cytotoxicity was similar to that observed with 5FU/FA alone. In
contrast, when HCT-8 cells were exposed to both agents simultaneously or to SN-38 followed by 5FU/FA, the cytotoxicity was
greater than that of SN-38 or 5FU/FA treatment alone. Investigation of the mechanistic basis for this sequence dependence
revealed that SN-38 treatment was associated with a dose- and time-dependent decrease in conversion of [5-3H]-2′-deoxyuridine to [3H]-H2O and thymidylate in intact cells. Immunoblotting failed to reveal any decrease in TS protein that could account for the decreased
activity. High-performance liquid chromatography revealed that SN-38 treatment was associated with increased levels of the
deoxynucleotide dTTP and decreased levels of dUTP. Flow microfluorimetry revealed that a 24-h treatment with 10 nM SN-38 resulted in accumulation of HCT-8 cells in late S and G2 phases of the cell cycle, with a further increase in the G2 fraction during the 24 h after SN-38 removal. Conclusions: These observations are consistent with a model in which SN-38 sequentially induces diminished DNA synthesis, elevated dTTP
pools, inhibition of dUMP synthesis and enhanced toxicity of 5FU/FA. Accordingly, sequencing of irinotecan and 5FU/FA might
be important in combining these agents into an effective treatment for colorectal cancer.
Received: 2 September 1997 / Accepted: 16 January 1998 相似文献
8.
Xie X Sasai K Shibuya K Tachiiri S Nihei K Ohnishi T Hiraoka M 《Cancer chemotherapy and pharmacology》2000,45(5):362-368
Purpose: Topoisomerase inhibitors including camptothecin are being studied as potential radiosensitizers. CPT-11 is a derivative
of camptothecin and is clinically available. In this study, we investigated the effects of SN-38 (an active metabolite of
CPT-11) on four nonirradiated and irradiated murine fibroblast cell lines with different p53 statuses to clarify the role
of p53 in the radiosensitizing activity of SN-38. Materials and methods: Four fibroblast cell lines, MT158, MT158/neo, MT158/wtp53 and MT158/mp53 with the same genetic background but with different
p53 statuses, were used. Exponentially growing cells were treated with SN-38 (200 nM) and incubated with the drug for 30 min. Cells were then irradiated (0 to 12 Gy) and further incubated with the drug for
2 h. The cell survival rate was determined using a conventional clonogenic assay. The effects of the treatments on the cell
cycle were analyzed with a flow cytometric assay. Apoptosis after these treatments was also detected by an annexin V assay.
Results: There were no significant differences in sensitivity to radiation or SN-38 treatment among these cell lines. The combined
treatment of irradiation and SN-38 showed supraadditive effects in all four cell lines independent of their p53 status. Transient
arrest in G2 with a decreased percentage of cells in both the S and G1 phases was observed 8 h after treatment with either SN-38 alone, radiation or their combination, regardless of the p53 status.
No significant differences in frequency of apoptosis were observed between treatment and control groups in two cell lines
with or without wild-type p53. Conclusion: The combination of irradiation and SN-38 treatment showed supraadditive effects in all four cell lines tested, and the p53
status did not play a role in the combination effect.
Received: 19 May 1999 / Accepted: 19 November 1999 相似文献
9.
In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems 总被引:7,自引:0,他引:7
Simona Romanelli Paola Perego Graziella Pratesi Nives Carenini Monica Tortoreto Franco Zunino 《Cancer chemotherapy and pharmacology》1998,41(5):385-390
Topotecan, a camptothecin analogue, is a␣specific inhibitor of topoisomerase I approved for use in the treatment of patients
with refractory ovarian carcinoma. The drug's mechanism of action suggests a potential efficacy of drug combinations incorporating
DNA-damaging agents. In an attempt better to define a␣rational basis for drug combination we examined the effect of topotecan
on the cytotoxicity and antitumor activity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor
xenograft. The in vitro cell system included a cisplatin-sensitive cell line, IGROV-1, and a cisplatin-resistant subline,
IGROV-1/Pt0.5, which is characterized by p53 mutation and loss of normal function of the wild-type gene of the parental cell
line. This cell system was chosen since the cell sensitivity to DNA-damaging agents appears to be dependent on p53 gene status.
Cytotoxicity was assessed by the growth inhibition assay using different schedules: (a) a 1-h period of cisplatin exposure
followed by a 24-h topotecan treatment and (b) a 1-h period of simultaneous exposure to cisplatin and topotecan. In the case
of the sequential schedule, an additive interaction was observed in IGROV-1 and IGROV-1/Pt0.5 cells. When the simultaneous
schedule was used, a synergistic interaction, more evident for the cisplatin-sensitive cells, was found. On the basis of these
observations at a cellular level, the effect of concomitant administration of the two drugs (i.e., the most favorable schedule)
was studied in the IGROV-1 tumor xenograft, which is moderately responsive to cisplatin and topotecan. Suboptimal doses of
each drug (with a low dose of topotecan, 5.1 mg/kg) achieved an antitumor effect comparable with or superior to that of the
optimal dose of a single treatment (tumor weight inhibition, 60%), thus indicating a␣pharmacological advantage of the combination
over the single treatment. However, an increase in the topotecan dose (7.1 mg/kg) was associated with an evident increase
in the toxicity of the combination, thereby suggesting that the drug interaction was not tumor-specific. Although the molecular
basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to
repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest
of topoisomerase I inhibitors in combination with cisplatin.
Received: 14 June 1997 / Accepted: 18 September 1997 相似文献
10.
Purpose: Cisplatin is a commonly used antineoplastic agent that acts by forming adducts with DNA, and causing a response to the cellular
injury. One of the components of this cellular injury response is the activation of the “growth arrest and DNA damage gene”GADD153. The level of GADD153 induction in tumor cells has been associated with the degree of cytotoxicity. The pupose of this study was to determine whether
cisplatin activates GADD153 also in nontumor cells and how GADD153 protein levels correlate with cisplatin-DNA adducts in different cell types. Methods: Nude mice with xenografted squamous cell carcinoma were treated with cisplatin 10 mg/kg. Tumors were removed at 0 h (untreated
controls), 24 h, and 48 h and immunohistochemically stained for GADD153 protein and cisplatin-DNA adducts. The staining reaction
was quantitated in tumor cells and nonmalignant stromal cells separately, using computerized image analysis. Results: The GADD153 level was 4.5 times higher in tumor cells than in stromal cells in untreated mice. At 24 h after cisplatin treatment
the GADD153 level had increased by 50% and 72% in tumor cells and stromal cells, respectively. Analysis of the cisplatin-DNA
adducts showed a reversed pattern, with six-fold higher levels in stromal cells than in tumor cells at 24 h after treatment.
By combining these data, we estimated that approximately 25-fold more GADD153 per cisplatin-DNA adduct was induced in tumor
cells than in stromal cells. Conclusion: Our data suggest that different cell types may respond differently to DNA damage caused by cisplatin.
Received: 5 March 1998 / Accepted: 21 July 1998 相似文献
11.
Naoko Masumoto Shuji Nakano Taito Esaki Hiromitsu Fujishima Takashi Tatsumoto Yoshiyuki Niho 《International journal of cancer. Journal international du cancer》1995,62(1):70-75
The combination of cis-diamminedichloroplatinum(II) (CDDP) and 7-ethyl-10-[4-(I -piperidino)-I -piperidino]carbonyloxycamptothecin (CPT-I I), a topoisomerase-l inhibitor, has been shown to be synergistic in vitro and clinically active against several human cancers refractory to chemotherapy. To elucidate the mechanism of the synergistic cytotoxicity of CDDP and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of CPT-11, we studied the interaction of these agents using an HST-I human squamous-carcinoma cell line. Cells were exposed to the IC50 concentration of SN-38 (5.0 ng/ml) for I hr and various concentrations of CDDP for 1 hr in several different treatment schedules. SN-38 augmented the anti-tumor activity of CDDP in all schedules, with maximal synergy observed with simultaneous administration. Evaluation of the kinetics of the removal of DNA interstrand cross-links, measured by alkaline elution, showed significant reduction of this removal in the cells exposed to SN-38 and CDDP, as compared with the cells exposed to CDDP alone. No differences, however, were found in the initially attained level of DNA interstrand cross-links induced by CDDP between these cells. Moreover, the intracellular accumulation of platinum measured by atomic-absorption spectrophotometry, was virtually identical between these cells. These results indicate that SN-38 can modulate the removal of platinum-DNA adducts, thereby potentiating the cytotoxicity of CDDP, suggesting a critical role for topoisomerase I in the repair of DNA interstrand cross-links. © 1995 Wiley-Liss Inc. 相似文献
12.
Yasuhiko Kano Miyuki Akutsu Saburo Tsunoda Koyoshi Mori Kenichi Suzuki Ken-Ichi Adachi 《Cancer chemotherapy and pharmacology》1998,42(2):91-98
Paclitaxel and irinotecan are important new anticancer agents. The combination of these two agents has been considered for
use against a variety of advanced solid tumors. Since the schedule-dependent effects of this combination may be crucial to
its use, we studied the interaction of paclitaxel and SN-38 (the active metabolite of irinotecan) in various schedules in
four human cancer cell lines in culture. Cell growth inhibition after 5 days was determined using an MTT assay. The effects
of drug combinations at the IC80 level were analyzed by the isobologram method. Simultaneous exposure to paclitaxel and SN-38 for 24 h produced antagonistic
(subadditive and protective) effects in the human lung cancer cell line A549, the breast cancer cell line MCF7, and the colon
cancer cell line WiDr, and produced additive effects in the ovarian cancer cell line PA1. Sequential exposure to paclitaxel
for 24 h followed by SN-38 for 24 h, and the reverse sequence, produced additive effects in all four cell lines. These findings
suggest that sequential administration, not simultaneous administration, may be the appropriate schedule for the therapeutic
combination of paclitaxel and irinotecan. Continued preclinical and clinical studies should provide further insights and assist
in determining the optimal schedule for this combination in clinical use.
Received: 25 February 1997 / Accepted: 6 November 1997 相似文献
13.
Hiroyuki Kohara Masahiro Tabata Katsuyuki Kiura Hiroshi Ueoka Kazuhiko Kawata Masakazu Chikamori Keisuke Aoe Kenichi Chikamori Akio Matsushita Mine Harada 《Clinical cancer research》2002,8(1):287-292
7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, a topoisomerase I (topo I) inhibitor, is one of the most active agent against lung cancer, and its radiosensitizing effect has been reported recently. We evaluated a combination in vitro effect of irradiation and 7-ethyl-10-hydroxy-CPT (SN-38), an active metabolite of 7-ethyl-10-[4- (1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, on a human small cell lung cancer cell line (SBC-3) and its cisplatin-resistant subline (SBC-3/CDDP). Growth-inhibitory effects of irradiation with or without SN-38 were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A modified isobologram method was used to evaluate the treatment interaction. The combination of irradiation and SN-38 showed a synergistic inhibitory effect on the growth of SBC-3/CDDP despite its cross-resistance to irradiation and SN-38. In contrast, the same combination showed only an additive effect on the growth of parental SBC-3 cells. There was no significant difference in topo I protein expression between these two cell lines. In SBC-3 cells, topo I catalytic activity was suppressed by 4 Gy of irradiation, without a decrease of nuclear topo I protein, whereas the exposure of SBC-3 cells to 1 microM SN-38 subsequent to irradiation showed no remarkable additional effects on both topo I activity and protein content. On the other hand, in SBC-3/CDDP cells, topo I activity was unchanged by irradiation, but the subsequent exposure to SN-38 gave rise to a decrease in topo I activity, which was accompanied by a significant decrease in the topo I protein content (P = 0.02). These observations may indicate that SN-38 induces sequestration of topo I onto DNA in radiation-treated SBC-3/CDDP cells and suggest that the synergistic effect of irradiation and SN-38 in SBC-3/CDDP cells was considered attributable to DNA repair-related enhanced recruitment of topo I onto the damaged DNA. 相似文献
14.
Purpose: The development of cisplatin resistance is a major problem in the treatment of cancer patients with cisplatin chemotherapy.
The membrane binding of terbium (Tb3+) has been shown to increase the cellular accumulation of cisplatin in breast cancer cells. Therefore, the ability of Tb3+ to modulate the cytotoxicity of cisplatin was investigated in cisplatin-sensitive (MDA) and cisplatin-resistant (MDA/CH)
MDA-MB-231 human breast cancer cells. Methods: The cytotoxic parameters of cisplatin were determined using live cell microfluorometry and median effect analysis. Results: MDA/CH cells (IC50 = 142 ± 9 μM) were found to be approximately 3.3-fold more resistant to cisplatin than MDA cells (IC50 = 43.5 ± 3.0 μM). In both cell lines, the IC50 value for cisplatin was reduced two-fold in the presence of 80 μM Tb3+, thus indicating that the cytotoxicity of cisplatin is increased by Tb3+. The cytotoxic activity of cisplatin alone was observed to be 5.7 and 1.6 times more potent than that of Tb3+ alone in MDA and MDA/CH cells, respectively. Combination index analyses revealed that the interaction between cisplatin and
Tb3+ was only synergistic at very low indices of cell death in MDA cells. However, in MDA/CH cells, the two drugs were synergistic
up to intermediate levels of cell death. Conclusions: Our results suggest that the enhancement of cisplatin cytotoxicity by Tb3+ is more effective in cisplatin-resistant MDA/CH cells than in cisplatin-sensitive MDA cells. Therefore, terbium is potentially
useful in cisplatin combination therapy for breast cancer patients, especially for those patients who have developed resistance
to the drug.
Received: 16 December 1998 / Accepted: 19 January 1999 相似文献
15.
Antiangiogenic potential of camptothecin and topotecan 总被引:11,自引:0,他引:11
Mark K. Clements Carleton B. Jones Melinda Cumming Sayed S. Daoud 《Cancer chemotherapy and pharmacology》1999,44(5):411-416
Purpose: To determine the inhibitory nature of sublethal doses of camptothecin (CPT) and topotecan (TPT) treatments on normal human
endothelial cells in vitro, as well as the in vivo antiangiogenic activity as compared to another antiangiogenic compound,
TNP-470 and to a nonspecific cytotoxic agent, cisplatin. Methods: Growth inhibition was determined by the crystal violet assay to measure relative cell numbers. 3H-thymidine uptake was used to determine the inhibitory effect of CPT and TPT on DNA synthesis in vitro. Cell viability was
determined using trypan blue exclusion assays. Cell cycle response to CPT was determined by flow cytometric analysis of propidium
iodide-stained nuclei. In vivo inhibition of angiogenesis was determined by the disc angiogenesis system (DAS), where surgical
sponge discs were placed subcutaneously in the rat dorsum and the ability of systemic treatment with liposomal CPT (LCPT),
TPT, TNP-470 or cisplatin to inhibit vascular growth into the discs was evaluated. Quantitation of vascular growth was determined
using toluidine blue staining of sectioned discs followed by digital image analysis. Results: Treatment with 50 nM CPT or TPT inhibited human umbilical venular endothelial cell (HUVEC) growth as shown by crystal violet staining, but was
not cytotoxic to the cells. This was evidenced by the fact that cell numbers did not increase or decrease with treatment,
but remained static while cells were viable for over 96 h posttreatment. 3H-thymidine uptake in HUVEC was inhibited as early as 5 min, reached a maximum inhibition at 24 h and lasted over 96 h posttreatment.
Cell cycle analysis of CPT-treated HUVEC showed arrest in S-phase at 12 h with a concurrent decrease in population of cells
in G1. Accumulation of cells at the G2/M-phase was discernible at 24 h along with the S-phase inhibition. Treatment of rats with 1 mg/kg LCPT or TPT every other
day for 14 days resulted in approximately 30% inhibition of vascular growth into the discs. This inhibition was similar to
the inhibition seen with TNP-470, an established and potent angiogenic inhibitor. In contrast, cisplatin was not as effective
in inhibiting vascular growth into the discs. Conclusions: In this work we showed that CPT and TPT inhibit human endothelial cell growth in vitro in a non-cytotoxic manner and that
this inhibition lasts more than 96 h after drug removal. We also showed that LCPT and TPT, unlike a nonspecific cytotoxic
agent, cisplatin, are as effective as TNP-470 in inhibiting angiogenic growth in the in vivo disc angiogenesis model. From
this observation we propose that in addition to their proven tumoricidal activities, camptothecins may have an indirect in vivo
antitumor effect mediated through the inhibition of angiogenesis.
Received: 1 October 1998 / Accepted: 8 March 1999 相似文献
16.
Kiyoshi Takasuna Takehiro Hagiwara Masaaki Hirohashi Michiyuki Kato Mamoru Nomura Eiichi Nagai Tsuyoshi Yokoi Tetsuya Kamataki 《Cancer chemotherapy and pharmacology》1998,42(4):280-286
Purpose: SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea
as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of β-glucuronidase, which hydrolyzes
detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics,
markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its
metabolites in rats treated with and without antibiotics. Methods: Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration
of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood,
intestinal tissues and intestinal luminal contents were determined by HPLC. Results: Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the
tissues or contents of the small intestine, which has less β-glucuronidase activity in its luminal contents. In contrast,
antibiotics markedly reduced the AUC1–24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete
inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. Conclusions: These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by β-glucuronidase in the intestinal
microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the
β-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.
Received: 8 August 1997 / Accepted: 16 January 1998 相似文献
17.
Simon P. Langdon Genevieve J. Rabiasz Alison A. Ritchie Uwe Reichert Peter Buchan William R. Miller John F. Smyth 《Cancer chemotherapy and pharmacology》1998,42(5):429-432
The activity of CD437{6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid}, a relatively selective activator
of RAR-γ, was evaluated against four human ovarian-carcinoma cell lines : PE01, PE04 (a Pt-resistant in vivo-derived counterpart
of PE01), PE01CDDP (a Pt-resistant in vitro-derived model of PE01) and PE014. Growth inhibition was observed after 3 and 6 days of exposure
to sub-micromolar concentrations as assessed by a reduction in cell number. IC50 values against PE01, PE04, PE01CDDP and PE014 were 0.09, 0.21, 0.12 and 0.28 μM (day 3) and 0.1, 0.14, 0.07 and 0.17 μM (day 6), respectively. Cisplatin-resistant cell lines were as responsive as cisplatin-sensitive lines, indicating potential
activity in resistant disease. CD437 was also evaluated against the PE04 xenograft grown in nude mice using daily doses of
20 (days 0–4) and 10 mg/kg (days 0–4 and 7–11) given either by i.p. delivery or oral administration. Significant growth inhibition
(P < 0.05) was obtained for both doses and by both routes. These data provide further support for the view that retinoids have
value for the treatment of ovarian cancer.
Received: 23 February 1998 / Accepted: 26 March 1998 相似文献
18.
Cisplatin-resistant KCP-4 cells were 12.4- and 31.6-fold more resistant to CPT-11 and SN-38 than parental KB-3-1 cells, respectively. We studied the mechanism of cross-resistance to CPT-11 and SN-38. Our previous study showed that multidrug resistance protein (MRP), canalicular multispecific organic anion transporter (cMOAT) and P-glycoprotein (P-gp) were not expressed in KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Chuman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The accumulation of both CPT-11 and SN-38 in KCP-4 cells was lower than that in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from KCP-4 cells was enhanced compared with that from KB-3-1 cells. DNA topoisomerase (topo) I expression, topo I activity, topo I-mediated cleavable complex, and the sensitivity to SN-38 of DNA topo I in KCP-4 were similar to those in KB-3-1 cells. Furthermore, the conversion of CPT-11 to SN-38 in the two cell lines was also similar. The transport of LTC4 in KCP-4 membrane vesicles was competitively inhibited by bis-(glutathionato)-platinum (II) (GS-Pt), CPT-11 and SN-38. These findings suggested that an unknown transporter distinct from P-gp, MRP or cMOAT is expressed in KCP-4 cells and transports CPT-11 and SN-38. 相似文献
19.
Clinton F. Stewart William C. Zamboni William R. Crom Peter J. Houghton 《Cancer chemotherapy and pharmacology》1997,40(3):259-265
The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone
in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38
lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice
were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently
obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence
detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and
the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed
biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan
lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and
a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1
l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability
was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 ± 0.67%,
whereas at 100 ng/ml the percent unbound was 1.18 ± 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma
xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals
after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present
study provide important information for the design of phase I studies of oral irinotecan.
Received: 30 August 1996 / Accepted: 27 November 1996 相似文献
20.
Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines 总被引:1,自引:0,他引:1
Zamboni WC Houghton PJ Hulstein JL Kirstein M Walsh J Cheshire PJ Hanna SK Danks MK Stewart CF 《Cancer chemotherapy and pharmacology》1999,43(4):269-276
Purpose: We have reported a 6-fold difference in the topotecan (TPT) lactone systemic exposure achieving a complete response in the
human neuroblastoma xenografts NB-1691 and NB-1643. However, the relationship between tumor extracellular fluid (ECF) exposure
to TPT and the antitumor activity in xenograft and in vitro models has not been established. Methods: TPT was given i.v. to mice bearing NB-1691 and NB-1643 tumors. Prior to dosing, microdialysis probes were placed in tumors
of mice bearing NB-1691 and NB-1643 tumors. Plasma and tumor ECF concentrations of TPT lactone were assayed by high performance
liquid chromatography. The inhibitory concentration (IC50) was determined for NB-1691 and NB-1643 cell lines in vitro. Results: The TPT AUCECF values determined for NB-1691 (n=10) and NB-1643 (n=11) were 7.3 ± 0.84 and 25.6 ± 0.76 ng h ml−1, respectively (P < 0.05). TPT tumor ECF penetration in NB-1691 and NB-1643 was 0.04 ± 0.04 and 0.15 ± 0.11 (P < 0.05), respectively. The IC50 values recorded after 6 h of TPT exposure daily for 5 consecutive days for NB-1691 and NB-1643 were 2.7 ± 1.1 and 0.53 ± 0.19 ng/ml,
respectively (P < 0.05). Conclusions: NB-1643 was more sensitive in vitro than NB-1691, and at similar plasma TPT exposures, NB-1643 had a greater degree of TPT
tumor ECF exposure and penetration as compared with NB-1691. Potential factors affecting tumor TPT ECF disposition include
tumor vascularity, capillary permeability, and interstitial pressure. The clinical importance of this study is underscored
by the need to select anticancer agents with a high capacity for tumor penetration and to optimize drug administration to
increase tumor penetration.
Received: 20 April 1998 / Accepted: 25 August 1998 相似文献