This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Agrawal, M. Articles by Chen, C. C. Search for Related Content PubMed PubMed Citation Articles by Agrawal, M. Articles by Chen, C. C.

Increased ^99mTc-Sestamibi Accumulation in Normal Liver and Drug-resistant Tumors after the Administration of the Glycoprotein Inhibitor, XR9576

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 [M. A., F. M. B., M. E., S. B., T. F.]; Mary Babb Cancer Center, West Virginia University, Charleston, West Virginia [J. A.]; Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel [W. D. S.]; and Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 [C. C. C.]

	ABSTRACT

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

 
^99mTc-sestamibi, a substrate of the multidrug transporter P-glycoprotein (Pgp), has been used as a functional imaging agent for the multidrug resistance-1 (MDR1) phenotype. In vitro, retention of ^99mTc-sestamibi by cells that overexpress Pgp can be enhanced by the addition of Pgp inhibitors. XR9576 (Tariquidar) is a potent and selective noncompetitive inhibitor of Pgp that is active at 25–80 nM. A Phase I trial of XR9576 in combination with vinorelbine (Navelbine) was conducted in 26 patients with metastatic cancers. A ^99mTc-sestamibi scan was obtained at baseline followed 48–96 h later by a second scan 1–3 h after the administration of XR9576. Time activity curves and areas under the curves (AUCs) were obtained for tumor, liver, lung, and heart, and tissue:heart AUC ratios were calculated. XR9576 enhanced ^99mTc-sestamibi accumulation and retention in the liver of all but two patients with a mean change of +128%. Furthermore, in 13 of 17 patients with tumor masses visible by ^99mTc-sestamibi, the tumor:heart ^99mTc-sestamibi AUC_{0–3 h} increased after the administration of XR9576, with increases of 36–263% seen in 8 patients. We conclude that in vivo administration of XR9576 inhibits ^99mTc-sestamibi efflux in both the normal liver and in drug resistant tumors. This study provides convincing evidence of the existence of XR9576-inhibitable ^99mTc-sestamibi efflux in a large fraction of drug resistant tumors. One can predict that efflux of Pgp substrates also occurs in these tumors. XR9576 provides an efficient way to inhibit this efflux and offers the potential to increase drug exposure in human cancer.

	INTRODUCTION

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

 
Drug resistance is a major impediment to chemotherapy in many human cancers. Pgp² , a 170-kDa membrane glycoprotein, encoded by the MDR-1 gene, is the most intensively studied mechanism of drug resistance. Pgp is an energy-dependent efflux pump that lowers the intracellular concentrations of a variety of chemotherapeutic agents, primarily natural products (1, 2, 3) . Expression of the MDR-1 gene at levels found in many clinical tumor samples can confer multidrug resistance in vitro, suggesting that MDR-1/Pgp-mediated drug resistance is clinically relevant.

The anthranilic acid derivative, Tariquidar (XR9576), is a potent and selective Pgp inhibitor that is being developed clinically for the treatment of multidrug-resistant tumors. At concentrations of 25–80 nM, XR9576 can restore the sensitivity of many multidrug-resistant human tumor cell lines to the anthracyclines, Vinca alkaloids, taxanes, and epipodophyllotoxins by inhibiting Pgp-mediated drug efflux (4 , 5) . The duration of action of XR9576 is superior to other inhibitors tested, persisting for at least 22 h after removal of drug from the culture medium. XR9576 uptake into cells is independent of Pgp expression, and the Pgp transport substrates vinblastine and paclitaxel only partially displaced the binding of XR9576 to Pgp. These data suggest that XR9576 is not a transport substrate of Pgp and that the XR9576-mediated inhibition of Pgp transport is noncompetitive.

First generation Pgp inhibitors such as verapamil and cyclosporine had potent pharmacological effects in addition to their ability to inhibit Pgp, and as a result, the dose of these agents was limited by toxicity. Third generation Pgp inhibitors such as XR9576 have been developed to specifically target Pgp and these agents appear to have minimal toxic effects, which are not dose limiting. The optimal dose of third generation Pgp inhibitors will be best assessed with in vivo assays that measure a drug’s ability to inhibit its target, Pgp, in tumor tissue or in a surrogate tissue. The recognition that ^99mTc-sestamibi, a radionuclide imaging agent marketed for evaluation of cardiac function and for breast imaging, is a Pgp substrate led to its development as an in vivo imaging agent for assessment of Pgp inhibition (6 , 7) .

In this study, we describe the use of ^99mTc-sestamibi imaging of the normal liver and tumors before and after the administration of XR9576 to assess the effect of XR9576 on Pgp-mediated efflux of this targeted imaging agent. ^99mTc-sestamibi scans showed enhanced retention of the tracer in liver and tumor, suggesting that Pgp-mediated drug efflux occurs in drug resistant tumors and can be modulated by nontoxic doses of XR9576.

	PATIENTS AND METHODS

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

 
Patients.
Twenty-six patients with metastatic cancer were enrolled in a Phase I study combining bolus vinorelbine (Navelbine) administered on a day 1, day 8 schedule with the Pgp antagonist XR9576. All patients consented to undergo two ^99mTc-sestamibi scans. Twenty-five patients had two ^99mTc-sestamibi scans and received protocol therapy; 1 patient, found to have brain metastases after enrollment, was removed from study and received radiation therapy. Patients initially had a baseline (pretreatment) ^99mTc-sestamibi scan. Forty-eight to 96 h later, a 150-mg dose of XR9576 alone was administered i.v., followed by a second ^99mTc-sestamibi scan 1–3 h later. In subsequent cycles, patients received a 150-mg i.v. dose of XR9576 administered over 30 min, beginning 60 min prior to the start of vinorelbine (Navelbine) on days 1 and 8 of a 4-week cycle.

Imaging.
Anterior and posterior images were acquired using low-energy/high resolution collimators and a 20% window centered over the 140-keV photopeak of ^99mTc. Large field of view, dual-headed cameras were used (ADAC Laboratories, Milpitas, CA). The same camera was used for both studies in all but 1 patient in whom the camera used at baseline malfunctioned.

Patients were positioned under the camera such that known metastatic lesions were in the field of view with the heart and liver also included whenever possible. Immediately after a bolus administration of 20 mCi of ^99mTc-sestamibi, 30 1-min sequential images were acquired. These were followed by 5-min spot images that were repeated at 1, 2, and 3 h after the administration of ^99mTc-sestamibi. A conventional whole body scan was also performed after the initial 30-min images.

Image Analysis.
Tumor visualization was determined by the nuclear medicine physician without knowledge of the results of other imaging procedures. In patients with tumor masses visualized by ^99mTc-sestamibi, one or more lesions were chosen for analysis. These were lesions that were visualized best and had the least overlap with other normal structures that took up ^99mTc-sestamibi. Using either anterior or posterior images, regions of interest were drawn over the metastatic lesions, normal liver, heart muscle, and lung when possible, and TACs were generated. Curves were background, decay, and dose corrected.

Using the corrected TACs, AUCs were calculated for 0–3 h for each TAC using the linear trapezoidal method. To compare ^99mTc-sestamibi uptake at baseline to that after XR9576 administration, a ratio of the AUC_{0–3 h} in tissue or tumor to the AUC_{0–3 h} heart was generated to yield tissue:heart AUC_{0–3 h}. Tissue and tumor AUCs were normalized to the heart muscle AUC to correct for the fact that 3-h images were not always acquired at exactly 180 min after sestamibi injection. Heart muscle was chosen because the heart contains relatively little Pgp and uptake into the heart should not be affected by XR9576 (8 , 9) . In two cases where the heart was not included in the initial 30 min of scanning, the raw AUC values were used.

The percentage change in liver:heart ^99mTc-Sestamibi AUC_{0–3 h} shown in Table 1 was calculated using the following formula: [(liver:heart AUC_{0–3 h} after XR) - (liver:heart AUC_{0–3 h} before XR)]/(liver:heart AUC_{0–3 h} before XR) x 100.

	RESULTS

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

Comparison of baseline scans with those performed after the administration of XR9576 showed no obvious visual changes in ^99mTc-sestamibi uptake and retention in normal lung or heart muscle. The lung:heart AUC_{0–3 h} in the right and left lungs also showed no substantial effect of XR9576 (mean percent change, right lung = +9%; left lung = +2%). For the heart, the mean change in AUC_{0–3 h} was +2%. In contrast, an increase in retention of ^99mTc-sestamibi was visibly apparent in the liver in almost all patients after XR9576 administration, and this was confirmed by a corresponding increase in liver:heart AUC_{0–3 h} ratios in 23 of 25 patients. As summarized in Table 1 , the mean (range) percentage change from baseline in liver:heart ^99mTc-sestamibi AUC_{0–3 h} was +128% (range, -14 to +278%). A substantial increase in ^99mTc-sestamibi accumulation was observed in most patients; however, the degree of enhancement of ^99mTc-sestamibi uptake by XR9576 was variable. Although patients received a fixed 150-mg dose of XR9576, there was no correlation between either body surface area or serum levels of XR9576 and the percentage change in liver:heart ^99mTc-sestamibi AUC_{0–3 h}.

In addition to enhanced hepatic accumulation of ^99mTc-sestamibi, tumor visualization was also frequently enhanced after XR9576 (Table 1 and Fig. 1 ). In 17 of 25 patients, at least one tumor mass was visualized and a ^99mTc-sestamibi AUC_{0–3 h} calculated. In three of these patients, the tumor was only visualized on the post XR9576 scan. Overall, ^99mTc-sestamibi imaging was able to detect tumor metastases in 17 patients. This included lung metastases in 63% of patients with radiographic documentation of lung lesions, and liver, lymph node, and bone/soft tissue foci in 40, 36, and 28% of patients with known disease in those areas, respectively. In some patients, liver lesions were seen as a photopenic defect.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Changes in 99mTc-sestamibi accumulations after XR9576 in the 33 tumors visualized and quantified in the 17 patients with visualized tumors categorized by tumor type. Each patient is represented by a different symbol. One to five lesions were quantified in each patient, and these are shown as individual data points, but all lesions from the same patient have the same symbol. The two data points identified as 5 and 10 represent lesions from patients 5 and 10. Images from these patients are shown in Fig. 2 . The "Other Cancers" group includes from left to right: ovarian carcinoma; non-small cell lung cancer; parotid gland carcinoma; basal cell carcinoma; and cervical adenocarcinoma.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. 99mTc-sestamibi images at baseline and after administration of XR95767 for patients 3, 5, and 10. Patient numbers are shown in parentheses. A, arrow identifies a left thigh mass that had gone undetected until the whole body 99mTc-sestamibi scan was performed (patient 3, renal cell carcinoma, 263% increase in tumor:heart AUC0–3 h ratio). B, arrow indicates a soft tissue mass invading the iliac bone (patient 5, renal cell carcinoma, 18% increase in tumor:heart AUC0–3 h ratio). C, arrows indicate numerous bilateral lung metastases that are all more readily visualized after the administration of XR9576 (patient 10, adrenocortical carcinoma, 76–191% increase in tumor:heart AUC0–3 h ratios).

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Effect of XR9576 on 99mTc-sestamibi disposition in normal heart and liver and two pulmonary metastases in a patient with adrenocortical carcinoma (patient 10). Administration of XR9576 has little effect on 99mTc-sestamibi accumulation in the heart but results in marked delay in hepatic clearance. The rapid decline in 99mTc-sestamibi levels in the tumors seen in the baseline scan is partially blocked by the administration of XR9576.

	DISCUSSION

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

For relatively nontoxic agents such as XR9576, the optimal dose would best be defined using a therapeutic end point rather than toxicity (maximum-tolerated dose), and a variety of in vivo and ex vivo assays to measure Pgp function and inhibition have been developed (5 , 6 , 14 , 15) . ^99mTc-sestamibi imaging has been used to evaluate the efficacy of Pgp inhibitors (16, 17, 18, 19) , and other studies have correlated ^99mTc-sestamibi imaging with either Pgp expression or clinical response. In breast cancer, several studies have correlated retention of ^99mTc-sestamibi with the levels of Pgp quantified by ¹²⁵I-labeled MRK-16 binding or more traditional immunohistochemical methods (20, 21, 22, 23, 24) . Trials evaluating primary and locally advanced breast cancer have demonstrated a correlation between Pgp expression and ^99mTc-sestamibi retention. In addition, several groups have reported that tumors that do not visualize with ^99mTc-sestamibi frequently do not respond to chemotherapy (25, 26, 27, 28, 29, 30) .

As previously shown for other antagonists, a marked effect was observed on ^99mTc-sestamibi accumulation in the normal liver, most likely reflecting inhibition of Pgp-mediated biliary excretion (16, 17, 18, 19 , 31) . In the absence of XR9576 (baseline studies), ^99mTc-sestamibi is rapidly taken up and then excreted from the liver; and after a period of efflux, ^99mTc-sestamibi levels in the liver are generally well below levels in the heart, which contains relatively little Pgp (32) . In contrast, after the administration of XR9576, ^99mTc-sestamibi accumulates in the liver and is retained there. The efflux of ^99mTc-sestamibi is the phase that is markedly affected by XR9576. It is clear that an XR9576-inhibitable efflux system, presumably Pgp, pumps ^99mTc-sestamibi out of the liver. However, close examination revealed that in 13 of 25 patients, the initial rate of liver uptake of ^99mTc-sestamibi in the baseline studies was faster than after the administration of XR9576. This suggests that an XR9576-inhibitable system may also be involved in the uptake of ^99mTc-sestamibi in the liver, raising the possibility that Pgp is also present and active at the blood/liver interface and mediates the accumulation of ^99mTc-sestamibi in the liver. Although unlikely, it should be noted that one cannot rule out alterations in hepatic blood flow after administration of XR9576 as an alternative explanation. More importantly, enhanced ^99mTc-sestamibi accumulations were seen in tumors in a majority of patients. The rapid efflux of ^99mTc-sestamibi from tumors at baseline was blocked after the administration of XR9576, likely representing blockage of Pgp-mediated efflux. The gradual decline of ^99mTc-sestamibi activity seen after the administration of XR9576 may represent non-Pgp mediated efflux, as sestamibi is known to be effluxed by a second ABC transporter, the multidrug resistance-associated protein, which is widely expressed and not blocked by XR9576 (33 , 34) . Our results raise two questions: (a) how sensitive is ^99mTc-sestamibi imaging to Pgp expression within tumors and (b) is the magnitude of the enhancement of accumulation of ^99mTc-sestamibi by a Pgp blocker significant? Although this Phase I study cannot provide an accurate estimate of sensitivity, some tentative conclusions can be reached. The accumulated data suggests that lung lesions are most likely to be successfully visualized. In this study, pulmonary metastases were detected by ^99mTc-sestamibi in 63% of patients with known lung metastases. Larger lesions are not necessarily easier to image as demonstrated by a patient with adrenocortical cancer who had too numerous to count lung metastases, many of which were visualized only after the administration of XR9576, whereas in other patients, larger metastases were not seen. ^99mTc-sestamibi was less successful in visualizing liver metastases, which were often seen as photopenic defects in the scans. This is likely because of the avid uptake of ^99mTc-sestamibi by normal liver. Finally, lymph node and bone or soft tissue metastases were detected with a sensitivity of 28–40%. Although some of these were ideally located in peripheral sites, overlapping sestamibi activity from the heart and the gastrointestinal tract often obscured others in the mediastinum and retroperitoneum. Attenuation by overlapping structures also undoubtedly contributed to the failure of many deep lesions to visualize with sestamibi. Also, because only one region could be chosen for the early 0–30-min images, lesions elsewhere in the body with rapid washout of sestamibi were likely missed by the whole body scan performed 30 min after the administration of ^99mTc-sestamibi. Thus, these sensitivities are likely to be underestimates.

As for the significance of the magnitude of the changes in uptake of ^99mTc-sestamibi after XR9576, several facts must be considered. The percentage increases in AUCs are for a 3-h period and thus represent an underestimation of the total increase. More importantly, however, is the fact that the results are based on planar imaging. Regions of interest drawn on planar images include all of the tissue between the tumor and the camera detector, as well as the tissue located behind the tumor in that plane. The inclusion of activity from these overlapping areas diminishes the magnitude of the changes in the tumor. Better results are expected in the future with the development of positron emission tomography using ^94mTc-sestamibi scanning, which will allow for true quantitation.

In summary, we report the evaluation of the ability of XR9576 to affect ^99mTc-sestamibi accumulation by various tissues and tumors. As has been previously reported with other Pgp antagonists, a marked effect was observed on the accumulation of ^99mTc-sestamibi in the liver of patients after the administration of XR9576. More importantly, the increases observed in tumors after the administration of XR9576 compare very favorably with those reported with previous Pgp antagonists, suggesting XR9576 might be a more potent antagonist than its predecessors (35) . The demonstration that ^99mTc-sestamibi accumulation can be increased by XR9576 provides evidence of the existence of inhibitable ^99mTc-sestamibi efflux and functioning Pgp in these drug-resistant tumors.

	Note added in proof:

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

 
XR9576 has been assigned the international nonproprietary name, Tariquidar.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Center for Cancer Research, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 402-1357; Fax: (301) 402-1608; E-mail: tfojo{at}helix.nih.gov

² The abbreviations used are: Pgp, P-glycoprotein; TAC, time activity curve; AUC, area under the curve; MDR1, multidrug resistance 1.

³ J. Abraham et al., manuscript in preparation.

Received 6/26/02; revised 9/24/02; accepted 10/ 1/02.

	REFERENCES

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Note added in proof: REFERENCES

 

1. Juliano R. L., Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta, 455: 152-162, 1976.[Medline]
2. Fojo A., Akiyama S., Gottesman M. M., Pastan I. Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res., 45: 3002-3007, 1985.[Abstract/Free Full Text]
3. Beck W. T., Mueller T. J., Tanzer L. R. Altered surface membrane glycoproteins in Vinca alkaloid-resistant human leukemic lymphoblasts. Cancer Res., 39: 2070-2076, 1979.[Abstract/Free Full Text]
4. Mistry P., Stewart A. J., Dangerfield W., Okiji S., Liddle C., Bootle D., Plumb J. A., Templeton D., Charlton P. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res., 61: 749-758, 2001.[Abstract/Free Full Text]
5. Martin C., Berridge G., Mistry P., Higgins C., Charlton P., Callaghan R. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br. J. Pharmacol., 28: 403-411, 1999.[CrossRef]
6. Piwnica-Worms D., Chiu M. L., Budding M., Kronauge J. F., Kramer R. A., Croop J. M. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res., 53: 977-984, 1993.[Abstract/Free Full Text]
7. Rao V. V., Chiu M. L., Kronauge J. F., Piwnica-Worms D. Expression of recombinant human multidrug resistance P-glycoprotein in insect cells confers decreased accumulation of technetium-99m-sestamibi. J. Nucl. Med., 35: 510-515, 1994.[Abstract/Free Full Text]
8. Beaulieu E., Demeule M., Ghitescu L., Beliveau R. P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem. J., 326: 539-544, 1997.
9. Sugawara I., Akiyama S., Scheper R. J., Itoyama S. Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett., 112: 23-31, 1997.[CrossRef][Medline]
10. Ferry D. R., Traunecker H., Kerr D. J. Clinical trials of P-glycoprotein reversal in solid tumours. Eur. J. Cancer, 32: 1070-1081, 1996.
11. Fisher G. A., Sikic B. I. Clinical studies with modulators of multidrug resistance. Hematol. Oncol. Clin. N. Am., 9: 363-382, 1995.[Medline]
12. Bradshaw D. M., Arceci R. J. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J. Clin. Oncol., 16: 3674-3690, 1998.[Abstract]
13. Fisher G. A., Lum B. L., Hausdorff J., Sikic B. I. Pharmacological considerations in the modulation of multidrug resistance. Eur. J. Cancer, 32: 1082-1088, 1996.[CrossRef]
14. Robey R., Bakke S., Stein W., Meadows B., Litman T., Patil S., Bates S. Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833. Blood, 93: 306-314, 1999.[Abstract/Free Full Text]
15. Chaudhary P. M., Mechetner E. B., Roninson I. B. Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood, 80: 2735-2739, 1992.[Abstract/Free Full Text]
16. Luker G. D., Fracasso P. M., Dobkin J., Piwnica-Worms D. Modulation of the multidrug resistance P-glycoprotein: detection with technetium-99m-sestamibi in vivo. J. Nucl. Med., 38: 369-372, 1997.[Abstract/Free Full Text]
17. Bakker M., van der Graaf W. T., Piers D. A., Franssen E. J., Groen H. J., Smit E. F., Kool W., Hollema H., Muller E. A., deVries E. G. 99mTc-Sestamibi scanning with SDZ PSC 833 as a functional detection method for resistance modulation in patients with solid tumours. Anticancer Res., 19: 2349-2353, 1999.[Medline]
18. Chen C. C., Meadows B., Regis J., Kalafsky G., Fojo T., Carrasquillo J. A., Bates S. E. Detection of in vivo P-glycoprotein inhibition by PSC 833 using Tc-99m sestamibi. Clin. Cancer Res., 3: 545-552, 1997.[Abstract]
19. Peck R. A., Hewett J., Harding M. W., Wang Y. M., Chaturvedi P. R., Bhatnagar A., Ziessman H., Atkins F., Hawkins M. J. Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin. J. Clin. Oncol., 19: 3130-3141, 2001.[Abstract/Free Full Text]
20. Del Vecchio S., Ciarmiello A., Pace L., Potena M. I., Carriero M. V., Mainolfi C., Thomas R., D’Aiuto G., Tsuruo T., Salvatore M. Fractional retention of technetium-99m-sestamibi as an index of P-glycoprotein expression in untreated breast cancer patients. J. Nucl. Med., 38: 1348-1351, 1997.[Abstract/Free Full Text]
21. Sun S. S., Hsieh J. F., Tsai S. C., Ho Y. J., Lee J. K., Kao C. H. Expression of mediated P-glycoprotein multidrug resistance related to Tc-99m MIBI scintimammography results. Cancer Lett., 153: 95-100, 2000.[CrossRef][Medline]
22. Sun S. S., Hsieh J. F., Tsai S. C., Ho Y. J., Kao C. H. Expression of drug resistance protein related to Tc-99m MIBI breast imaging. Anticancer Res., 20: 2021-2025, 2000.[Medline]
23. Ciarmiello A., Del Vecchio S., Silvestro P., Potena M. I., Carriero M. V., Thomas R., Botti G., D’Aiuto G., Salvatore M. Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer. J. Clin. Oncol., 16: 1677-1683, 1998.[Abstract]
24. Vecchio S. D., Ciarmiello A., Potena M. I., Carriero M. V., Mainolfi C., Botti G., Thomas R., Cerra M., D’Aiuto G., Tsuruo T., Salvatore M. In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients. Eur. J. Nucl. Med., 24: 150-159, 1997.[CrossRef][Medline]
25. Burak Z., Ersoy O., Moretti J. L., Erinc R., Ozcan Z., Dirlik A., Sabah D., Basdemir G. The role of 99mTc-MIBI scintigraphy in the assessment of MDR1 overexpression in patients with musculoskeletal sarcomas: comparison with therapy response. Eur. J. Nucl. Med., 28: 1341-1350, 2001.[CrossRef][Medline]
26. Kao C. H., Tsai S. C., Wang J. J., Ho Y. J., Ho S. T., Changlai S. P. Evaluation of chemotherapy response using technetium-99M-sestamibi scintigraphy in untreated adult malignant lymphomas and comparison with other prognosis factors: a preliminary report. Int. J. Cancer, 95: 228-231, 2001.[CrossRef][Medline]
27. Kao C. H., Tsai S. C., Liu T. J., Ho Y. J., Wang J. J., Ho S. T., ChangLai S. P. P-Glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings. Cancer Res., 61: 1412-1414, 2001.[Abstract/Free Full Text]
28. Yamamoto Y., Nishiyama Y., Satoh K., Takashima H., Ohkawa M., Fujita J., Kishi T., Matsuno S., Tanabe M. Comparative study of technetium-99m-sestamibi and thallium-201 SPECT in predicting chemotherapeutic response in small cell lung cancer. J. Nucl. Med., 39: 1626-1629, 1998.[Abstract/Free Full Text]
29. Nishiyama Y., Yamamoto Y., Satoh K., Ohkawa M., Kameyama K., Hayashi E., Fujita J., Tanabe M. Comparative study of Tc-99m MIBI and TI-201 SPECT in predicting chemotherapeutic response in non-small-cell lung cancer. Clin. Nucl. Med., 25: 364-369, 2000.[CrossRef][Medline]
30. Komori T., Narabayashi I., Matsui R., Sueyoshi K., Aratani T., Utsunomiya K. Technetium-99m MIBI single photon emission computed tomography as an indicator of prognosis for patients with lung cancer-preliminary report. Ann. Nucl. Med., 14: 415-420, 2000.[Medline]
31. Kabasakal L., Halac M., Nisli C., Oguz O., Onsel C., Civi G., Uslu I. The effect of P-glycoprotein function inhibition with cyclosporine A on the biodistribution of Tc-99m sestamibi. Clin. Nucl. Med., 25: 20-23, 2000.[CrossRef][Medline]
32. Fojo A. T., Ueda K., Slamon D. J., Poplack D. G., Gottesman M. M., Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA, 84: 265-269, 1987.[Abstract/Free Full Text]
33. Hendrikse N. H., Franssen E. J., van der Graaf W. T., Meijer C., Piers D. A., Vaalburg W., deVries E. G. 99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein. Br. J. Cancer, 77: 353-358, 1998.[Medline]
34. Utsunomiya K., Ballinger J. R., Piquette-Miller M., Rauth A. M., Tang W., Su Z. F., Ichise M. Comparison of the accumulation and efflux kinetics of technetium-99m sestamibi and technetium-99m tetrofosmin in an MRP-expressing tumour cell line. Eur. J. Nucl. Med., 27: 1786-1792, 2000.[CrossRef][Medline]
35. Stewart A., Steiner J., Mellows G., Laguda B., Norris D., Bevan P. Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration. Clin. Cancer Res., 6: 4186-4191, 2000.[Abstract/Free Full Text]

This article has been cited by other articles:

				J. Abraham, M. Edgerly, R. Wilson, C. Chen, A. Rutt, S. Bakke, R. Robey, A. Dwyer, B. Goldspiel, F. Balis, et al. A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine Clin. Cancer Res., May 15, 2009; 15(10): 3574 - 3582. [Abstract] [Full Text] [PDF]

				D. M. Hermann Review: Future perspectives for brain pharmacotherapies: implications of drug transport processes at the blood--brain barrier Therapeutic Advances in Neurological Disorders, November 1, 2008; 1(3): 167 - 179. [Abstract] [PDF]

				J. P. Bankstahl, C. Kuntner, A. Abrahim, R. Karch, J. Stanek, T. Wanek, W. Wadsak, K. Kletter, M. Muller, W. Loscher, et al. Tariquidar-Induced P-Glycoprotein Inhibition at the Rat Blood-Brain Barrier Studied with (R)-11C-Verapamil and PET J. Nucl. Med., August 1, 2008; 49(8): 1328 - 1335. [Abstract] [Full Text] [PDF]

				C. Bolzati, M. Cavazza-Ceccato, S. Agostini, S. Tokunaga, D. Casara, and G. Bandoli Subcellular Distribution and Metabolism Studies of the Potential Myocardial Imaging Agent [99mTc(N)(DBODC)(PNP5)]+ J. Nucl. Med., August 1, 2008; 49(8): 1336 - 1344. [Abstract] [Full Text] [PDF]

				S. Shukla, C.-P. Wu, K. Nandigama, and S. V. Ambudkar The naphthoquinones, vitamin K3 and its structural analogue plumbagin, are substrates of the multidrug resistance linked ATP binding cassette drug transporter ABCG2 Mol. Cancer Ther., December 1, 2007; 6(12): 3279 - 3286. [Abstract] [Full Text] [PDF]

				E. F. Choo, D. Kurnik, M. Muszkat, T. Ohkubo, S. D. Shay, J. N. Higginbotham, H. Glaeser, R. B. Kim, A. J. J. Wood, and G. R. Wilkinson Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1012 - 1018. [Abstract] [Full Text] [PDF]

				L. Hong, Y. Piao, Y. Han, J. Wang, X. Zhang, Y. Du, S. Cao, T. Qiao, Z. Chen, and D. Fan Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2 Mol. Cancer Ther., December 1, 2005; 4(12): 1936 - 1942. [Abstract] [Full Text] [PDF]

				V. Sharma, J. L. Prior, M. G. Belinsky, G. D. Kruh, and D. Piwnica-Worms Characterization of a 67Ga/68Ga Radiopharmaceutical for SPECT and PET of MDR1 P-Glycoprotein Transport Activity In Vivo: Validation in Multidrug-Resistant Tumors and at the Blood-Brain Barrier J. Nucl. Med., February 1, 2005; 46(2): 354 - 364. [Abstract] [Full Text] [PDF]

				D. Peer, Y. Dekel, D. Melikhov, and R. Margalit Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models Cancer Res., October 15, 2004; 64(20): 7562 - 7569. [Abstract] [Full Text] [PDF]

				S. E. Bates, S. Bakke, M. Kang, R. W. Robey, S. Zhai, P. Thambi, C. C. Chen, S. Patil, T. Smith, S. M. Steinberg, et al. A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma Clin. Cancer Res., July 15, 2004; 10(14): 4724 - 4733. [Abstract] [Full Text] [PDF]

				A. Pichler, J. L. Prior, and D. Piwnica-Worms Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine PNAS, February 10, 2004; 101(6): 1702 - 1707. [Abstract] [Full Text] [PDF]

				G. D. Leonard, T. Fojo, and S. E. Bates The Role of ABC Transporters in Clinical Practice Oncologist, October 1, 2003; 8(5): 411 - 424. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Agrawal, M. Articles by Chen, C. C. Search for Related Content PubMed PubMed Citation Articles by Agrawal, M. Articles by Chen, C. C.