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1 Departments of Pharmaceutical Sciences, 2 Molecular Pharmacology, 3 Hematology-Oncology, 4 Pathology, and 5 Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recently Ehrlichman et al. (21) showed that another ERBB1 inhibitor, CI-1033, belonging to the same structural class (4-anilinoquinazolines) as gefitinib, reversed SN-38 resistance through inhibition of the ABCG2 transporter [also termed breast cancer resistance protein (22) , MXR (23) , or ABCP (24) ] that transports certain camptothecin analogs out of cells. Most ABC transporters are localized on cellular membranes and transport structurally diverse compounds. They are composed of either one or two membrane spanning domains and one or two ATP-binding domains that function as either a single protein or a multiprotein complex (25) . The so-called "half-molecule" transporters within the ABC superfamily (i.e., containing only one membrane spanning and one ATP-binding domain) are typically localized to the membranes of intracellular organelles (26) . However, ABCG2 is the only half-molecule transporter localized to the plasma membrane (27 , 28) .
In the present study we have examined the effect of gefitinib on the antitumor activity of irinotecan. Our studies indicate that the combination of gefitinib with irinotecan results in markedly enhanced antitumor activity of irinotecan in multiple tumor models. Furthermore, oral dosing of gefitinib significantly increases the oral bioavailability of irinotecan. Emerging clinical data indicate greater response rates in children treated with protracted schedules of topotecan and irinotecan administration (9, 10, 11, 12) . However, camptothecins such as irinotecan are characterized by relatively poor and highly variable oral bioavailability. The results presented here suggest that gefitinib, through inhibition of ABCG2, will increase the oral bioavailability of irinotecan.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Growth Inhibition Studies.
CB17/Icr female scid–/– mice received implantation subcutaneously with a single tumor fragment, as described previously (29
, 30)
. Mice bearing subcutaneous tumors each received irinotecan when tumors were approximately 0.20 to 1 cm diameter. The procedures have been reported previously (5)
. Tumor-bearing mice were randomized into groups of seven before therapy. All mice were maintained under barrier conditions. Protocols and conditions approved by the St. Jude Children’s Research Hospital, institutional animal care and use committee were used to conduct all experiments. Mice were followed for up to 12 weeks after starting treatment.
Tumor Response and Tumor Failure Time.
A partial response was defined as a 
50% decrease in tumor volume but with measurable tumor (0.10 cm3) remaining at all times. Complete response was defined as a disappearance of measurable tumor mass (<0.10 cm3) at some point within 12 weeks after initiation of therapy. Maintained complete response was complete response without tumor regrowth within the 12-week study time frame. If an initial tumor volume was <0.20 cm3, data on that tumor were excluded. Tumor failure time was defined as the time (in weeks) required by individual tumors to quadruple their volume from the initiation of therapy. Tumor failure times were termed as censored if a mouse died before week 12 and before a tumor grew to four times its initial volume.
Statistical Methods.
To compare time to tumor failure for different treatment regimens, the exact log-rank test was used to compare the survival distributions of each treatment group with the survival distribution of the control group. The Bonferroni procedure to adjust for the multiplicity of tests of significance within each tumor line/study was used to maintain experiment-wise significance level at 0.05. SAS version 6.12 and StatXact-4 were used for statistical analysis.
Drug Formulation and Administration.
The parenteral clinical formulation of irinotecan was generously provided by Dr. J. P. McGovren (Pharmacia, Kalamazoo, MI). Irinotecan was diluted in sterile saline and administered intravenously (0.1 ml/10 g of body weight) at dosages ranging from 0.06 to 5 mg/kg as a short injection (duration of administration was <1 minute) into lateral tail vein daily for 5 days on 2 consecutive weeks followed by a 9 day rest period. This is referred to as 1 cycle of therapy [abbreviated (dx5)2]. Mice received 3 cycles [abbreviated [(dx5)2]3] over a period of 8 weeks (31)
. Alternatively, irinotecan was administered by oral gavage, as described previously (32
, 33)
. Gefitinib was provided by AstraZeneca (Alderley Park, Cheshire, United Kingdom). Gefitinib was dissolved in DMSO (10% v/v final concentration) and diluted in carboxymethylcellulose (0.25% w/v) to a final concentration of 20 mg/ml. Gefitinib was administered by oral gavage either as a single dose (100 mg/kg) or twice daily (100 mg/kg/dose) for 5 days/week throughout the experiment designated (d x 5)N.
Detection of ERBB1–4 in Xenograft Tissues.
Standard techniques (34)
of Western blotting were used to analyze 100 µg of protein lysate per sample. Primary antibodies included ERBB1 and ERBB2 mouse monoclonal antibodies (NovaCastra, Newcastle-upon-Tyne, United Kingdom) and ERBB3 and ERBB4 rabbit polyclonal antibodies (Santa Cruz Biotechnology, Santa Cruz, CA). Phospho-Y1173 mouse and ERBB1 phospho-Y1248 rabbit and phospho-Y1173 ERBB1 mouse antibodies, respectively (Cell Signaling Technology, Beverly, MA), were used to detect active phosphorylated ERBB1 and ERBB2 receptors. ß-Actin was used as a protein-loading and transfer control. The A431 (ERBB1), SKBR3 (ERBB2, ERBB3), and MHH-MED-1 (ERBB4) human cell lines were used as positive controls for ERBB receptor expression.
Detection of ABCG2 in Xenograft Tissues.
Formalin-fixed paraffin-embedded tissue sections were stained with rabbit polyclonal anti-ABCG2 (35)
. A biotin-conjugated goat antirabbit secondary antibody was used and streptavidin-horse radish peroxidase detection system was used to develop the 3-amino-9-ethylcarbazole color. Slides were incubated in 3% hydrogen peroxide, avidin-biotin blocking system (DAKO, Carpinteria, CA) and with 5% goat serum to eliminate cross-reactive background staining. An irrelevant rabbit IgG was applied instead of primary antibody as a negative control, and a known positive breast carcinoma was used as a positive control.
Cell Culture.
The human osteosarcoma cell line, Saos-2, was obtained from American Type Culture Collection (HTB-85, American Type Culture Collection, Manassas, VA), and cells were maintained in DMEM (Biowhitaker, Walkersville, MD) containing 10% fetal bovine serum, 1% penicillin/streptomycin, and 2 mmol/L glutamine (Invitrogen, Carlsbad, CA). Saos2 derivatives engineered to overexpress functional ABCG2 (#4) or equal expression of a Walker mutant that is not a functional transporter (10#mut) have been described previously (35)
. Derivative cell lines were grown in the presence of 500 µg/ml G418.
Reversal of ABCG2-Mediated Resistance to SN-38.
To screen compounds for the ability to reverse the ABCG2 phenotype, Saos-2 cells transfected with either ABCG2#4, ABCG2Mut#10, or PCDNA#3 (vector control) were plated in 96-well Costar plates. One thousand cells per well were added in 0.1 ml of growth medium and allowed to attach overnight. The next morning the used medium was gently aspirated, and serial dilutions of the compounds tested were added. In these experiments, each cell type was dosed with SN-38 or SN-38 plus gefitinib. Twenty-four hours later drug-containing medium was aspirated, and 0.1 ml of medium without drug was added. After an additional 5-day incubation, 10 µL of Alamar blue (Biosource, Camarrilo, CA) was added aseptically, and the plates were returned to the incubator for 6 hours. The amount of the fluorescent dye produced was measured on a Cytofluor 2300 (Millipore, Bedford, MA) with an excitation wavelength of 530 nm and emission wavelength of 590 nm.
Accumulation and Efflux of [14C]Gefitinib.
Two milliliters of cell suspension containing either Saos2 ABCG2#4 or Saos2 Mut#10 (5 x 105 cells) were plated in Falcon 35 x 10 mm Multiwell 6-well tissue culture plates (Becton Dickinson, Franklin Lakes, NJ). After attachment overnight at 37°C, medium was aspirated and cells were washed twice with 2 ml of physiologic Tris buffer [20 mmol/L Tris containing 120 mmol/L NaCl, 3 mmol/L K2HPO4, 0.5 mmol/L MgCl2, 1 mmol/L CaCl2, and 10 mmol/L glucose (pH 7.4)]. Monolayers were incubated at room temperature in physiologic Tris for 10 minutes before aspiration of buffer and replacement with 1 ml serum-free RPMI 1640 HEPES buffer [10.4 g RPMI 1640 in 1 liter 25 mmol/L HEPES (pH 7.4)] containing 0.5 µCi/ml [14C]gefitinib (specific activity, 91.5 µCi/mg; final concentration, 1 µmol/L; generously provided by AstraZeneca) with or without 10 mmol/L NaN3 (36)
. After the appropriate period of incubation at room temperature, medium was rapidly aspirated to terminate drug accumulation. For efflux studies, cells were incubated with [14C]gefitinib for 5 minutes at which time medium was aspirated and replaced with drug-free medium to determine the rate of drug efflux. To determine cellular radiolabel content in accumulation and efflux studies, cells were washed 10 times with ice-cold PBS and drained before addition of 1 ml trypsin-EDTA (0.05% trypsin, 0.53 mmol/L EDTA). After 5 minutes, monolayers were triturated to give a uniform suspension, and 0.75 ml was used to determine radioactivity by scintillation counting. Cell number was determined with 200 µL of cell suspension.
Pharmacokinetic Studies.
Irinotecan disposition was evaluated in nontumor-bearing CB17/Icr scid–/– mice after a single gefitinib dose (100 mg/kg). Irinotecan (10 mg/kg) was administered as a short infusion in the lateral tail vein (duration of infusion <1 minute) or by oral gavage. Blood (
1 mL) was collected with heparinized syringes from three animals per time point. For all intravenous studies, samples were collected pre, 0.25, 1, 2, 4, and 6 hours after infusion. For all oral studies, samples were collected pre, 0.25, 0.5, 1, 2, 4, and 6 hours after administration. In both the intravenous and oral studies, the irinotecan dosage was 10 mg/kg. All blood samples were handled and processed as described previously (33
, 37)
. The irinotecan and SN-38 lactone plasma concentrations were determined by an isocratic high-performance liquid chromatography assay with fluorescence detection as described previously in detail (33
, 37)
. The lower limit of quantitation was 1 ng/mL for irinotecan and SN-38. All calibrators and controls were prepared in murine plasma (Hill Top Lab Animals, Inc. Scottdale, PA).
Pharmacokinetic Analysis.
Pharmacokinetic parameters were calculated with the NONMEM program (Version V; ref. 38
). A four-compartment model was used to fit irinotecan and SN-38 plasma concentration versus time data. Compartmental parameters estimated included clearance (CL), volume (V), bioavailability (F), absorption rate constant (ka), intercompartmental rate constants (kcp, kpc) for irinotecan, and apparent elimination rate for SN-38 [k40/FF; FF = formation fraction (i.e., irinotecan fraction converted to SN-38)]. Nonlinear-mixed effects modeling was used to estimate the pharmacokinetic parameters of each drug and to determine whether treatment with gefitinib (GEF) was a significant covariate on these parameters. This method was used because the study used a destructive sampling approach (39)
. With this study design, estimates of inter-subject variability were indeterminable. We chose to fix intra-subject variability at a relative error of 10% (related to assay error) and an absolute error of 0.1 µg/ml (related to assay level of detection), and the inter-subject variability was fixed at 15% CV. To determine whether gefitinib significantly affected the clearance and bioavailability of irinotecan, we used the following covariate models: CL = 
1 + GEF·2 and F = 3 + GEF·4 where GEF is 0 when gefitinib is not present and 1 when it is present.
To determine whether gefitinib was a statistically significant covariate, we evaluated whether the addition of gefitinib significantly reduced the negative 2 log likelihood [e.g., a decrease of 3.84 indicates a significant difference (P < 0.05) based on the 
2 test]. We also tested whether the parameters representing the gefitinib effects (2 and 4) were significantly different from 0 (i.e., i > 1.96 · SEMi) indicating a significance based on the t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. For some experiments, growth of control tumors was rapid, necessitating termination of mice at day 14. Consequently T/C values are presented for the last day of control tumor measurement as indicated. Growth of NB-1382 tumors was most inhibited, whereas growth of OS1 osteosarcoma xenografts was somewhat increased compared with controls.
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. Greater than additive activity was determined in SJ-GBM2 (P = 0.003), NB-1691 (P = 0.014), Rh28 (P = 0.018), and NB-1382 (P = 0.003). For Rh18 tumors the combination showed enhanced biological activity over irinotecan alone, but failed to reach statistical significance (P = 0.12). Representative results are shown in Fig. 1
. Similarly, the combination caused enhanced antitumor activity compared with irinotecan alone, against OS17 and OS21 xenografts. Whereas irinotecan induced growth stasis without regressions, the combination caused maintained complete responses, but the difference between groups treated with irinotecan alone or the combination did not reach significance (P = 0.14, and 0.17, respectively); in part this was because of irinotecan demonstrating substantial activity that prevented tumors reaching the criteria for defining failure (i.e., growth by 400%) within the 12-week period of observation (Fig. 2)
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. Of importance is that ERBB1 expression was not detected in any xenograft tissue (GBM2 was not evaluated). ERBB3 and ERBB4 were detected only in NB-1691 tumors. Consistent with clinical observations (40)
, activated ERBB2 receptor was detected in three of the osteosarcoma xenografts. Thus, the apparent synergy cannot be associated with ERBB1 receptor expression. Immunostaining for ABCG2 expression showed strong expression of the transporter in NB-1691, OS-17, and OS21 (Fig. 4)
as well as OS29 (not shown). Moderate or weak staining appeared in OS-1 and Rh18 (not shown), whereas very weak staining was detected in Rh28, NB-1382 and SJ-GBM2 samples (not shown).
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, Saos2 cells expressing the nonfunctional transporter (ABCG2#10mut) were sensitive to SN38, and the concentration causing 50 per cent decrease in cell proliferation (IC50) was approximately 3 nmol/L. In these cells, increasing gefitinib concentrations marginally decreased sensitivity to SN-38 (e.g., SN-38 IC50 increased to 9.5 nmol/L in the presence of 5 µmol/L gefitinib). As depicted in Fig. 5B
, Saos2 cells expressing functional transporter (ABCG2#4) were 30-fold resistant to SN-38 relative to ABCG2#10mut cells (IC50 = 100 nmol/L). Furthermore, coincubation with gefitinib completely reversed resistance to SN-38. Gefitinib had essentially no effect on the sensitivity of vector transfected control Saos2 cells to SN-38 (data not shown).
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, the accumulation of [14C]gefitinib reached steady state by 5 minutes and was similar in both cell lines. Reduction of cellular ATP with sodium azide decreased accumulation of [14C]gefitinib in both cell lines. At the concentrations evaluated, efflux of [14C]gefitinib was similar in both ABCG2#10mut and ABCG2#4 clones. These results suggest that gefitinib is not a substrate for ABCG2-mediated transport.
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. Irinotecan oral bioavailability increased from 0.25 ± 0.06 to 0.87 ± 0.21, a 63% increase (P < 0.001). In addition, we also noted an increase in SN-38 plasma concentrations as depicted in Fig. 7B
. Results of our pharmacokinetic modeling showed this increase was because of the increase in parent drug, not to an increase in SN-38 formation or decrease in SN-38 elimination.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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These results led us to investigate the possibility that gefitinib altered the cellular resistance to irinotecan. Previous studies had shown that a structurally similar ERBB1 inhibitor, CI-1033, inhibits ABCG2 in vitro (21)
. Immunohistochemical staining revealed quite robust expression of ABCG2 in NB-1691, and three osteosarcoma lines. Of significance is that immunocytochemical staining6
was used to detect ABCG2 in 80% of osteosarcoma specimens (n = 20). Thus it is possible that gefitinib potentiates irinotecan activity by reversing cellular resistance, at least in some of the tumors examined (NB-1691, OS17, OS21), but not necessarily in SJ-GBM2, or NB-1382 where ABCG2 expression was very low. Obviously, other transporters such as ABCB1 (P-glycoprotein), which may not be inhibited by gefitinib at pharmacologic concentrations, may confer cellular resistance to SN-38.
To test whether gefitinib could inhibit ABCG2 directly, we determined whether gefitinib could reverse SN-38 resistance mediated by ABCG2 in vitro. Saos2 cells that do not express either ABCG2 or P-glycoprotein were stably transfected with human ABCG2. In addition, a clone (ABCG2#10mut) expressing similar levels of a nonfunctional ABCG2 was used as a negative control. Clones expressing ABCG2 were resistant to SN-38. Importantly, gefitinib (1 µmol/L) potently reversed resistance to SN-38 in ABCG2#4. In contrast, gefitinib marginally protected ABCG2#10mut-expressing cells from SN-38. Thus, the ability of gefitinib to reverse resistance to SN-38 was dependent on expression of functional ABCG2. Of interest is that the accumulation and efflux of radiolabeled gefitinib was similar whether or not a functional ABCG2 transporter was expressed. Furthermore, use of sodium azide to deplete ATP, and hence reduce outward transport mediated by ABC transporters, actually decreased the accumulation of [14C]gefitinib. These data suggest that gefitinib is an inhibitor but not a substrate for ABCG2.
In accordance with Jonker and colleagues (42) , we observed Abcg2 mRNA expression in the small intestine and kidney (data not shown). The presence of Abcg2 was confirmed with both immunoblot and immunohistochemical analysis in the kidney and small intestine (data not shown). These results provide a basis for the ability of gefitinib to modulate oral bioavailability of irinotecan through the inhibition of Abcg2 in the small intestine.
On the basis of our preclinical results and the observations by Schellens et al. (43) that an inhibitor of ABCG2, elacridar (GF120918), increased topotecan oral bioavailability, we examined whether gefitinib would have a similar effect on irinotecan oral bioavailability. Results obtained in nontumor bearing mice show that gefitinib increases irinotecan bioavailability from 0.25 to 0.87 after a single gefitinib dose. Because of presystemic activation of irinotecan (44) , SN-38 plasma exposures were higher after oral dosing compared with a similar dose of irinotecan administered intravenously. An alternative explanation is that gefitinib could increase oral bioavailability by inhibiting metabolism of irinotecan through inhibition of cytochrome P450 (Cyp3a13A11, 3A13, 3A16) in mouse intestine. However, given the prominent apical expression of ABCG2 in the enterocytes and the potent inhibition of ABCG2 by gefitinib in cultured cells that lack the capacity to metabolize irinotecan, we consider this less likely. Moreover, it is likely that the major Cyp3A metabolite (an O-desmethyl) of gefitinib is just as capable of inhibiting ABCG2 when one considers that it retains strong ability to inhibit epidermal growth factor receptor-tyrosine kinase activity (45) .
We have shown previously that protracted schedules of administration increase efficacy of several camptothecin analogs including irinotecan (5 , 7 , 46 , 47) . These results are consistent with these agents exerting specific S-phase cytotoxicity (2) . Thus, treatment daily for two consecutive 5-day courses was more effective than treatment for only 5-consecutive days, despite the cumulative dose in each treatment group being identical. Similar results are emerging from clinical trials of these agents in children where protracted (dx5x2) courses are demonstrating promising antitumor-response rates (12 , 48) . However, oral dosing of irinotecan is limited because of, in part, poor oral bioavailability and large interpatient variability (49 , 50) . Potentially, gefitinib may act to modulate oral bioavailability of irinotecan in patients and overcome some of these limitations.
In summary, our results show that combination of gefitinib and irinotecan results in greater than additive antitumor activity in tumor models and that activity is independent of tumor ERBB1 status. Consistent with results of another 4-anilinoquinazoline, CI-1033 (21) , gefitinib inhibits the ABCG2 drug transporter. Hence, this may be a common mechanism for this chemical class of tyrosine kinase inhibitors. Consequently, it may not be possible to relate results of clinical trials where ERBB1 inhibitors are combined with classical cytotoxic agents to effects on the primary target kinases. Importantly, gefitinb increases the oral bioavailability of irinotecan. Potentially, this effect may enhance oral absorption and decrease interpatient variability, thus providing a means to optimize scheduling of these agents in patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Requests for reprints: Peter J. Houghton, Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 North Lauderdale St., Memphis, TN 38105. Phone: 901-495-3463; Fax: 901-521-1668; E-mail: peter.houghton{at}stjude.org
6 J.J. Jenkins, N.C. Daw, V.M. Santana, P.J. Houghton, J.D. Schuetz, unpublished results. 
Received 1/13/04. Revised 8/10/04. Accepted 8/19/04.
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K.-i. Fujita, Y. Ando, M. Narabayashi, T. Miya, F. Nagashima, W. Yamamoto, K. Kodama, K. Araki, H. Endo, and Y. Sasaki GEFITINIB (IRESSA) INHIBITS THE CYP3A4-MEDIATED FORMATION OF 7-ETHYL-10-(4-AMINO-1-PIPERIDINO)CARBONYLOXYCAMPTOTHECIN BUT ACTIVATES THAT OF 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO]CARBONYLOXYCAMPTOTHECIN FROM IRINOTECAN Drug Metab. Dispos., December 1, 2005; 33(12): 1785 - 1790. [Abstract] [Full Text] [PDF]
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N. C. Daw, W. L. Furman, C. F. Stewart, L. C. Iacono, M. Krailo, M. L. Bernstein, J. E. Dancey, R. A. Speights, S. M. Blaney, J. M. Croop, et al. Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children's Oncology Group Study J. Clin. Oncol., September 1, 2005; 23(25): 6172 - 6180. [Abstract] [Full Text] [PDF]
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C.-H. Yang, C.-J. Huang, C.-S. Yang, Y.-C. Chu, A.-L. Cheng, J. Whang-Peng, and P.-C. Yang Gefitinib Reverses Chemotherapy Resistance in Gefitinib-Insensitive Multidrug Resistant Cancer Cells Expressing ATP-Binding Cassette Family Protein Cancer Res., August 1, 2005; 65(15): 6943 - 6949. [Abstract] [Full Text] [PDF]
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R. R. Vethanayagam, H. Wang, A. Gupta, Y. Zhang, F. Lewis, J. D. Unadkat, and Q. Mao FUNCTIONAL ANALYSIS OF THE HUMAN VARIANTS OF BREAST CANCER RESISTANCE PROTEIN: I206L, N590Y, AND D620N Drug Metab. Dispos., June 1, 2005; 33(6): 697 - 705. [Abstract] [Full Text] [PDF]
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, Control; 
, gefitinib; 
, irinotecan; 
, gefitinib + irinotecan.
, 3 µmol/L; 
, 5 µmol/L gefitinib. Cell viability was enumerated after 5 days (mean ± SD).
