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Clinical Cancer Research Vol. 5, 3352-3356, November 1999
© 1999 American Association for Cancer Research

Advances in Brief

Rapid Activation of MDR1 Gene Expression in Human Metastatic Sarcoma after in Vivo Exposure to Doxorubicin1

Amir Abolhoda2, Amy E. Wilson2, Howard Ross, Peter V. Danenberg, Michael Burt and Kathleen W. Scotto3

Departments of Surgery [A. A., H. R., M. B.] and Molecular Pharmacology and Therapeutics [A. E. W., K. W. S.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and The Kenneth Norris Jr. Cancer Research Institute, University of Southern California School of Medicine, Los Angeles, California 90089 [P. V. D.]


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Overexpression of P-glycoprotein (Pgp), a multidrug transporter encoded by the MDR1 gene, is associated with chemoresistance in some human solid tumor malignancies. To date, analyses of MDR1 levels in solid tumors have examined constitutive increases in expression at relapse. In the present study, we have evaluated the acute induction of MDR1 gene expression in a solid human tumor as a function of time in response to in vivo exposure to chemotherapy. Five patients with unresectable sarcoma pulmonary metastases underwent isolated single lung perfusion with doxorubicin. Relative MDR1 gene expression was measured in metastatic tumor nodules and normal lung specimens after initiation of chemoperfusion. In four of five patients, a 3–15-fold (median, 6.8) increase in MDR1 RNA levels was detected in tumors at 50 min after administration of doxorubicin. In contrast, normal lung samples had very low levels of MDR1 RNA prior to perfusion, and no acute increases were observed after therapy. These findings demonstrate, for the first time, that MDR1 gene expression can be rapidly activated in human tumors after transient in vivo exposure to cytotoxic chemotherapy.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The development of MDR4 in cancer patients represents a major obstacle to successful cancer chemotherapy. Although acquired MDR is a well-documented clinical phenomenon, the molecular events mediating in vivo tumor response and subsequent emergence of tumor chemoresistance are presently ill defined. Of the many models of drug resistance studied, overexpression of Pgp, encoded in humans by the MDR1 gene, is frequently implicated in the acquisition of the MDR phenotype in human cancer cell lines (reviewed in Refs. 1 and 2 ). Increased levels of Pgp are thought to confer resistance to tumor cells by decreasing net intracellular accumulation of a variety of structurally and functionally unrelated antineoplastic agents, including anthracyclines (e.g., doxorubicin), Vinca alkaloids, epipodophyllotoxins, and antibiotics. Despite the large body of evidence in support of the role of Pgp overexpression in MDR in vitro, the clinical relevance of MDR1 gene expression has not been clearly elucidated. Although there is good evidence for a correlation between MDR1 expression and chemoresistance in tumors of the hematopoetic lineage (3) , a multitude of retrospective clinical studies have demonstrated a wide spectrum of MDR1 RNA and protein levels in solid tumor malignancies (1 , 2) . Furthermore, several reports have identified MDR1 gene overexpression as an independent negative prognostic factor in clinical outcome (4, 5, 6, 7) . However, a major limitation in the design and interpretation of these conventional clinical studies has been the time lag between the administration of chemotherapeutic agents and the determination of MDR1 status. In other words, these studies represent static measurements of gene expression and have not addressed the immediate molecular events occurring in the in situ tumor bed in response to acute drug exposure. Therefore, in light of recent studies demonstrating acute activation of the MDR1 gene in vitro in response to chemotherapy (8, 9, 10, 11) , we have evaluated the increase in MDR1 gene expression in vivo during acute drug exposure. Five patients with sarcoma pulmonary metastases received an acute course of high-dose doxorubicin delivered via an ILP circuit. Using a semiquantitative reverse transcription-PCR method, we measured MDR1 RNA levels in normal lung and metastatic tumor nodules of these patients immediately before and after chemoperfusion. This study represents the first attempt to examine the possibility that MDR1 gene expression is rapidly activated after acute in vivo exposure of a human solid malignancy to cytotoxic chemotherapy.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patients and Tissue Procurement.
Between June 1995 and February 1997, five patients with sarcoma pulmonary metastases underwent ILP with doxorubicin as part of an ongoing Phase I trial at Memorial Sloan-Kettering Cancer Center. This Institutional Review Board-approved protocol enrolls patients with pathologically documented metastatic sarcoma to the lung, not amenable to resection, to receive organ-specific cytotoxic chemotherapy via an isolated perfusion circuit. Fig. 1Citation is a schematic representation of the perfusion technique. Through a left thoracotomy, the left main pulmonary artery and both pulmonary veins were isolated, proximally occluded, and individually cannulated. Just prior to the initiation of the doxorubicin perfusion (i.e., time 0), tumor and normal lung wedge biopsies were obtained. The doxorubicin solution was then delivered through the pulmonary artery at a rate of 500–1000 ml/min for a period of 10–20 min, followed by a 10-min wash-out with buffered Hespan (6% hetastarch in 0.9% sodium chloride). Additional tumor and normal lung biopsies were obtained at 20 and 50 min after the initiation of the doxorubicin chemoperfusion. The procured tumor nodules were trimmed from adjacent normal tissue, frozen immediately by immersion in liquid nitrogen, and stored at -70°C. Normal lung specimens were preserved separately in a similar manner. At the completion of the wash-out phase, the vessels were decannulated, the arteriotomy and venotomies were repaired, and all clamps were removed to reestablish pulmonary circulation. Subsequently, the chest incision was closed in a standard fashion. Clinical tumor response was evaluated radiographically by postoperative computed tomography of the chest.



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  		Fig. 1. Schematic representation of the isolated lung perfusion circuit. Sup., superior.

 
Tissue Doxorubicin Measurements.
A portion of each frozen sample was processed for measurement of tissue doxorubicin levels as follows (12) . The tissue was homogenized by a Polytron tissue homogenizer (Brinkmann Instruments, Westbury, NY) in 0.02 M KH2PO4 buffer (pH 3.8; 1:5 w/v). Forty µl of internal standard (daunorubicin, 10 mg/liter; Cerubidine; Wyeth Laboratories, Philadelphia, PA), 30 µl of KH2PO4, 60 µl of 33% silver nitrate, and 390 µl of 80% acetonitrile in water were added to 300 µl of tissue homogenate. Samples were vortexed and centrifuged for 10 min at 3000 rpm to precipitate proteins. Fifty-µl aliquots of the supernatant were analyzed by high-performance liquid chromatography using a Waters pump series 510 and an Autosampler 717 (Waters Corp., Milford, MA). Detection was performed with a Waters 470 scanning fluorescence detector at an excitation wavelength of 480 nm and an emission wavelength of 560 nm. The stationary phase was Zorbax Phenyl (3 mm) packed in a stainless-steel tube (6-mm inside diameter x 40-mm length). The mobile phase was 28% acetonitrile in 0.34 M phosphoric acid solution at a flow rate of 1.0 ml/min. Data were collected and calculated using the Millennium version 2.10 program (Waters Corp.) and expressed as the ratio of the peak area to that of the internal standard. All assays were performed in duplicate and reported as mean concentrations.

Quantitation of MDR1 Gene Expression by Reverse Transcription-PCR Assay.
Frozen tissue specimens were pulverized in a steel mortar situated on a bed of liquid nitrogen. Total cellular RNA was isolated by the guanidinium thiocyanate-phenol-chloroform extraction method of Chomczynski and Sacchi (13) . MDR1 mRNA levels were quantitated using the technique described by Horikoshi et al. (14) Briefly, each RNA isolate was reverse-transcribed into cDNA using random hexanucleotide primers. Serial dilutions of the newly synthesized cDNA (3-fold dilutions for MDR1; 10-fold dilutions for standards) were then used as substrates for independent PCR amplification of MDR1 and internal standards ({beta}-actin and GAPDH). The PCR primers were synthesized by Integrated DNA Technologies, Inc.(Coralville, IA). Each 5' primer contained the T7 polymerase promoter sequence 5'-TAATACGACTCACTATA-3', linked to a transcription initiation sequence (the next four to six bases), which functioned to improve the yield of the amplified gene fragment {approx}500 fold when the PCR product was transcribed with T7 polymerase. The primer sequences for MDR1 and {beta}-actin genes used in these experiments have been reported previously (15) . The 5' and 3' primers for GAPDH were T7–5'-GGGACATCTCTGCCCCCTCTGCTG-3' and 5'-CCCTCCGACGCCTGCTTCAC-3', respectively. PCR amplification and T7 RNA polymerase transcription were performed as described previously (14) . [{alpha}-32P]CTP-labeled transcription products were electrophoresed on a 6% denaturing polyacrylamide gel containing 8 M urea. The gels were dried and exposed to film. The bands representing the products of MDR1, {beta}-actin, and GAPDH amplification were excised and counted in a liquid scintillation counter. The linear amplification range for MDR1 and the internal standards was established for each of the cDNA samples. Relative gene expression was calculated by determining the ratio between the amount of the radiolabeled PCR product within the linear amplification range of MDR1 and the internal standard genes. Each cDNA was subjected to a minimum of two independent PCR analyses. Although the absolute numbers obtained from duplicate or triplicate experiments sometimes differed, the relative numbers (i.e., fold activation) were always similar.


   Results
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Discussion
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Table 1Citation summarizes the clinicopathological and dose-response characteristics of the five patients. Primary histologies included one visceral, one truncal, and three extremity soft tissue sarcomas. Four of the five patients (patients 1, 2, 4, and 5) had received prior treatment, with doxorubicin as a major component of the chemotherapeutic regimen. On the basis of a dose escalation protocol, the first four patients underwent lung perfusion with doxorubicin at 40 mg/m2; the fifth patient received the 80 mg/m2 dose. The most recent computed tomography evaluations of the chest have revealed progression of disease in the perfused lung of all five patients.


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  		Table 1 Patient clinicopathological and dose-response characteristics

 
To verify the effectiveness of ILP as a drug delivery system, tissue levels of doxorubicin were measured using high-performance liquid chromatography; microgram amounts of doxorubicin were detected in the normal lung and tumor specimens obtained at various times after initiation of chemoperfusion (Table 2)Citation . The general trend for the lower tissue doxorubicin levels at 50 min is most likely a result of the Hespan wash-out, during which time most of the unbound drug was cleared from the pulmonary microcirculation.


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  		Table 2 Mean tissue concentrations of doxorubicin (mg/gm) after isolated lung perfusion

 
Quantitative analysis of the mRNA isolates from untreated tumor samples (i.e., time 0) in the first four patients revealed a 3-fold variation in baseline expression of the MDR1 gene when normalized to the expression of a {beta}-actin control (Fig. 2)Citation ; patient 5 had no detectable MDR1 RNA levels prior to perfusion. At 20 min after initiation of doxorubicin perfusion, a noticeable rise in the MDR1:{beta}-actin mRNA ratio was observed in the first four patients (Fig. 2A)Citation . Moreover, this rise was further augmented and sustained at 50 min after doxorubicin exposure, at which time MDR1 RNA was also detected in the tumor specimen from patient 5. To assure that the relative differences measured were not a consequence of changes in expression of the control {beta}-actin gene, MDR1 RNA levels were also normalized to the expression of a second control gene, GAPDH. Although there was some variation in the absolute levels of activation when normalized against each standard gene, essentially the same pattern of MDR1 gene activation was noted (Fig. 2, A and B)Citation . It is important to note that in normal lung specimens, which contained very low intrinsic levels of MDR1 transcript, no acute increase in MDR1 mRNA levels was observed during or after chemoperfusion (data not shown). Fig. 2DCitation depicts the distribution of the fold increases in relative MDR1 gene expression as a function of time after exposure of the metastatic tumor nodules to doxorubicin. A median 4- and 6.8-fold increase in MDR1 RNA levels was observed within 20 and 50 min, respectively, after the initiation of chemoperfusion.



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  		Fig. 2. Time-dependent changes in the relative MDR1 gene expression in tumor samples of the patients undergoing isolated lung perfusion with doxorubicin. A, MDR1 gene expression relative to {beta}-actin. The PCR products are 157 and 232 bp, respectively. B, MDR1 gene expression relative to GAPDH. C, representative autoradiogram of labeled MDR1 and {beta}-actin PCR products of cDNA serial dilutions (3-fold dilutions for MDR1; 10-fold dilutions for {beta}-actin) at 0, 20, and 50 min after tumor exposure to doxorubicin. The data shown are from patient 2. D, scatter-plot of the distribution of the fold increases in MDR1:{beta}-actin ratio in the tumor nodules of those patients showing MDR1 gene induction. Thick black bar, median value at each time point.

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The overexpression of genes associated with the development and maintenance of drug resistance phenotypes has been attributed to the selection and subsequent clonal expansion of preexisting drug-resistant cells (16) Although several drugs, by virtue of their mutagenic properties, have been suggested to increase the frequency with which these subpopulations arise, the possibility that chemotherapeutics may actually induce drug-resistant variants has remained largely unexplored. However, a number of recent studies indicating that the expression of the MDR1 gene can be rapidly and transiently induced in cultured cell lines exposed to a variety of chemotherapeutic agents (8, 9, 10, 11) prompted us to investigate the possibility that development of de novo clinical chemoresistance may be, at least in part, mediated by direct induction of MDR1 gene expression by antineoplastic agents.

Patients with sarcoma pulmonary metastases demonstrated acute up-regulation of MDR1 mRNA in response to a transient in vivo course of chemotherapy. It is interesting to note that all five patients had progression of disease, despite high-dose chemoperfusion. Although lack of clinical response in this Phase I trial cannot be solely attributed to the observed increase in MDR1 expression, our findings are consistent with a clinical correlation between MDR1 overexpression and tumor chemoresistance. It should also be noted that, unlike what has been suggested by some in vitro studies, previous exposure to chemotherapy is not a prerequisite for gene activation, because patient 3 had not received prior treatment, yet demonstrated a similar induction of MDR1 expression. Therefore, the possibility exists that acute activation of MDR1 expression may play a role in both intrinsic and acquired drug resistance.

The mechanism underlying the rapid increase in MDR1 mRNA levels in human tumors during chemotherapy has yet to be investigated. Because steady-state levels of mRNA are determined by both the rate of synthesis and the rate of degradation, a change in either of these two pathways could account for the observed increase in gene expression. However, several observations lead us to favor transcriptional activation of the MDR1 promoter as the target of chemotherapeutic challenge: (a) countless studies of gene expression have indicated that regulation at the level of gene transcription is the primary means by which cells rapidly respond to changes in their environment; (b) a number of studies in cultured cell lines have indicated that the MDR1 promoter can be activated by a variety of stress inducers, including heat shock, heavy metals, differentiating agents, and chemotherapeutic agents (reviewed in Ref. 17 ). Indeed, we have shown recently that the transcription factors NF-Y and SP1 and the transcriptional coactivator P/CAF mediate activation of the MDR1 promoter by UV and chemotherapeutics (18) ; and (c) the relatively long half-life of MDR1 mRNA in cultured cells suggests that an increase in mRNA stability in response to drug challenge would not result in a notable increase in MDR1 mRNA levels within the time course of our studies. We are presently investigating the possible mechanisms of activation of the MDR1 gene by chemotherapeutics both in cultured cells and in an equivalent in vivo rodent model of isolated lung perfusion (19) .

The clinical implications of our findings are far-reaching. Although the surgical operative time limitations of our model did not allow an extended evaluation of the course of MDR1 gene activation and subsequent measurements of Pgp synthesis, corresponding in vitro studies indicate that induction of MDR1 mRNA levels by chemotherapeutic agents is most often accompanied by increases in Pgp protein levels (9) . Moreover, this activation is reversible, and expression decreases over time after drug removal (9) . If this is true in the clinical setting, it suggests that alternative drug delivery schedules and the use of chemosensitizing agents could potentially abrogate the tumor response in favor of the host. Although the initial Phase I trials of Pgp reversal agents have had limited clinical success because of suboptimal tissue concentrations and significant dose-limiting toxicities, the new generation of MDR chemomodulators, including cyclosporin A and its potent analogue PSC 833, have been shown to prevent induction of a number of genes, including MDR1 (20) . With a more detailed molecular understanding of MDR1 gene regulation, particularly with respect to the cellular factors involved in MDR1 gene activation in response to chemotherapeutic challenge, these new resistance modifiers may assume a greater role in the armamentarium of the clinical oncologist.

This study represents the first observation of a rapid induction of MDR1 gene expression in a solid human tumor in response to chemotherapeutic exposure. Additional studies are required to determine the generality of this effect, with respect to both chemotherapeutic agent and tumor type, as well as the kinetics of MDR1 RNA and protein induction and its impact on therapeutic outcome. Nevertheless, this observation has the potential to create a critical shift in our approach to the evaluation of MDR1 gene expression in clinical samples and suggests that tumor types in which a clear correlation between MDR1 expression and chemoresistance has not been demonstrated should be reevaluated for a possible role of acute, and possibly transient, MDR1 induction in clinical response. Clarification of the precise mechanisms involved in MDR1 gene activation should allow us to prevent or effectively modulate tumor chemoresistance, which will translate into improved clinical response.


   ACKNOWLEDGMENTS
 
We thank Dr. William Tong for performing the HPLC analyses. We dedicate this report to the memory of the late Dr. Michael Burt, a superb surgeon and a wonderful colleague, mentor, and friend.


   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 This work was supported by Grants NIH-NCI P01 CA 49179 (to M. B.), NIH-NCI R01 CA 57307 (to K. W. S.), and NIH-NCI F32 CA 67489 (to A. E. W.). Back

2 These authors contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Laboratory of Eukaryotic Transcription, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8972; Fax: (212) 639-2767; Back

4 The abbreviations used are: MDR, multidrug resistance; MDR1, multidrug resistance-1; Pgp, P-glycoprotein; ILP, isolated single lung infusion; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Back

Received 3/15/99; revised 6/ 9/99; accepted 6/14/99.


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 Results
 Discussion
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