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Biochemistry |
Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037 [C. S. J., B. C. G.]; Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [B. J. V., W. D. B.]; and Cell and Cancer Biology Department, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850 [T. M.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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184,500. The total number of expected deaths from prostate cancer this year is 39,200. The current methods of diagnosis include digital rectal examination and prostate-specific antigen blood test. The effective treatment of prostate cancer requires early detection and accurate staging of the disease. Generally, at the clinical presentation, the majority of patients have disease that has extended beyond the prostate, i.e., local or distant metastases. Many early-stage prostate tumors require androgen for survival, and therapies that are designed to interfere with steroid metabolism have been effective. Most prostate cancer patients, however, show relapse of disease and acquire a more aggressive androgen-independent metastatic disease (1)
. There is no currently available curative therapy; therefore, the development of new diagnostic imaging agents for accurate staging and new cytotoxic therapies is of utmost importance. The diagnosis of soft tissue primary or metastatic prostate carcinoma or even its residual/recurrent lesions after radical prostectomy is currently limited by routine diagnostic modalities, such as magnetic resonance imaging, computed tomography, and ultrasound. The skeletal metastases are routinely diagnosed with radionuclide skeletal imaging. However, the soft tissue metastases and involvement of pelvic lymph nodes cannot be accurately assessed with current techniques. Therefore, there is a need for a reliable noninvasive diagnostic procedure to determine the lymphatic and soft tissue spread of prostate neoplasm. Accurate, early detection of prostate tumor and its metastases would improve patient management and outcome of therapy. Recently, the 111In-labeled murine antibody 7E11-C5.3-GYK (conjugated to diethylenetriaminepentacetic acid linker chelator), which binds to prostate-specific antigen, was clinically studied and approved by the Food and Drug Administration under the commercial name "ProstaScint" for clinical staging and management of patients with prostate tumors (2, 3, 4) . However, this product has several limitations, such as slow clearance of antibody from the plasma, high uptake in liver and intestine, production of human antimouse antibodies in some patients, the need for repeat patient imaging up to 5 days postinjection, and the high cost of the drug. Radiolabeled small molecule(s) peptide or nonpeptide certainly would be preferred because of their rapid clearance from the blood pool and normal organs.
Sigma receptors are nonopiate, nondopaminergic, membrane-bound proteins that possess high affinity for haloperidol and various other neuroleptics (5) . It is known that there are at least two sigma receptors subtypes, termed sigma-1 and sigma-2 (6) . Sigma-1 sites can be selectively labeled by [3H](+)-pentazocine, whereas DTG3 is a non-subtype-selective ligand for labeling both sigma-1 and sigma-2 sites (7 , 8) . Sigma-2 sites can be labeled with the use of [3H]DTG in the presence of dextrallorphan, which masks the labeling of sigma-1 sites (8) . Sigma receptors are present not only in central nervous system but also in other tissues, such as the liver, kidneys, lungs, gonads, and ovaries (9 , 10) . The endogenous sigma-ligand(s) are not known; however, progesterone has been suggested to be a candidate (11) . The pharmacological significance of sigma receptor-binding sites remain elusive due to lack of functional and structural information. However, recently, the sigma-l binding site, a Mr 30,000 protein from guinea pig liver, was purified and cloned. The amino acid sequence of this protein showed no homology to any known mammalian proteins, but a partial homological resemblance with a fungal protein involved in sterol synthesis was observed (12) .
On the basis of in vitro pharmacological binding studies with tritiated ligands, we recently discovered that sigma receptors are expressed in high densities (1.0–1.5 million receptors/cell) on androgen-dependent (LNCaP) human prostate tumor cells (13) . Therefore, we reasoned that the compounds binding sigma receptors with a modest to high affinity could be potentially used for in vivo labeling of such receptors, thereby enabling noninvasive imaging of human prostate tumor sites. In addition, sigma sites could be an attractive target not only for diagnostic imaging but also for therapeutic intervention. Sigma receptors are also expressed in a variety of other human tumors, such as malignant melanoma (13 , 14) , non-small cell lung carcinoma (15) , breast (16 , 17) , and tumors of neural origin (18) . Pharmacological binding studies with membrane preparations from biopsied tumors tissue and the corresponding normal tissues have indicated that sigma receptors are overexpressed with respect to normal tissue (19 , 20) .
Sigma receptor-binding ligands have also shown the inhibition of proliferation in mammary adenocarcinoma (MCF-7 and MDA-MB-231), colon carcinoma cells (LIM l2l5 and WIDr), melanoma cells, and neural tumor cells in culture (21 , 22) . These results have implicated that sigma binding sites may play an important role in cell growth, differentiation, and cell proliferation as well. Here, we evaluated the noninvasive imaging potential of three radioiodinated benzamides in a nude mouse model hosting prostate tumor xenografts. The therapeutic potential of one of the sigma-binding ligands was also evaluated in three different prostate cell colonogenic assays.
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MATERIALS AND METHODS |
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Chemical Synthesis
Preparation of PIMBA (1)
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PIMBA was prepared as described previously (23)
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Synthesis of N-[2-(1'-Piperidinyl)ethyl]-4-methoxy-3-trimethyl stannylbenzamide (2)
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A mixture of PIMBA (1; 500 mg, 1.3 mmol), tetrakis(triphenylphosphine)-palladium(0) (150 mg, 0.13 mmol, 10% molar equivalent), bis(trimethylstannyl) (510 mg, 1.5 mmol), triethylamine (50 ml), and THF (50 ml) was heated at reflux overnight. The reaction mixture was evaporated to dryness in vacuum. The residue was dissolved in ethylacetate and eluted on a silica gel column loaded with hexanes. The column was first eluted with hexanes (50 ml) and then EtOAc:NEt3 (9:1) to give a light yellow oil. 1H NMR (CDCl3) yielded: 0.266 (s, 9H, Me3); 1.42–1.47 (m, 2H, CH2); 1.56–1.59 (m, 4H, CH2); 2.42–2.55 (m, 6H, CH2); 3.46–3.49 (s, 2H, NCH2); 3.81 (s, [3H], OMe); and 6.80–7.79 (m, 4 H, NH and arom).
Radiochemical Synthesis of [125I]PIMBA (3)
[125I]PIMBA was prepared using the following method. An ethanolic solution of N-[2-(1'-piperidinyl)ethyl]-4-methoxy-3-trimethyl stannylbenzamide (2; 1 mg/ml) was prepared. To 50 µl of this solution was added Na125I (0.5–1.0 mCi, 3–5 ml) in 0.1 N NaOH, followed by the addition of 0.05 N HCl (100 µl) to adjust to pH 4.0–5.5. A freshly prepared solution (100 µl) of chloramine-T (1 mg/ml) was added to the above mixture, and the solution was incubated at room temperature for 15 min. After this time, 200 µl of sodium metabisulfite (3 mg/ml) were added, and the solution was incubated for an additional 5 min. Finally, a saturated solution of sodium bicarbonate (500 µl) was added to reaction vial, and the radioactivity was extracted with chloroform (2 x 1 ml). The organic layer was separated and evaporated with a stream of argon. The residue was dissolved in methanol (400 µl) and injected into HPLC fitted with a reverse-phase C18 column and eluted with methanol-Tris buffer (10 mM, pH 5.5; 80:20, v/v). The retention time at a flow rate of 1.0 ml/min was 9 min. The fractions containing the desired compound were pooled together and cospotted on TLC along with authentic nonradioactive and developed in CHCl3:methanol (90:10). The Rf of nonradioactive and [125I]PIMBA was found to be 0.85 in the above solvent system. The chemical synthesis and structures of all three benzamides are shown in Fig. 1
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Pharmacology
In Vitro Sigma-1 Binding Assay.
Guinea pig brain membranes (300–500 µg of protein) were incubated with 3 nM [3H](+)-pentazocine (51.7 Ci/mmol) in 0.5 ml of 50 mM Tris-HCl (pH 8.0) for 120 min at 25°C. PIMBA was added in concentrations ranging from 10-4 to 10-12 M. Assays were terminated by the addition of 5 ml ice-cold 10 mM Tris-HCl (pH 8.0) and filtered through glass fiber filters using a Brandel cell harvester (Gaithersburg, MD). Filters were then washed twice with 5 ml of ice-cold 10 mM Tris-HCl (pH 8.0). The nonspecific binding was determined in the presence of 10 µM haloperidol. The filters were soaked in 0.5% polyethyleneimine for at least 30 min at 25°C prior to use. Scintillation counting was carried out in Ecoscint (National Diagnostics, Manville, NJ) after an overnight extraction of counts. Protein concentration was determined by the Lowry method.
In Vitro Sigma-2 Binding Assay.
Rat liver homogenates (150–200 µg of protein) were incubated with 3 nM [3H]DTG (39.4 Ci/mmol) in the presence of 1 µM dextrallorphan (to mask sigma-1 sites). The procedure was same as above. IC50s were determined using the computerized iterative curve-fitting program GraphPad InPlot4 (GraphPad Software, San Diego, CA). Ki was calculated from IC50s using Cheng-Prusoff equation.
Scatchard Analysis of Binding of Tritiated Sigma Ligands in Human Prostate Tumor (DU-145) Cell Membranes.
Crude membranes from DU-145 cells were prepared as follows: homogenization of cells (Potter-Elvehjem homogenizer with Teflon pestle) was carried out in ice-cold 10 mM Tris-HCl (pH 7.4). The homogenate was centrifuged at 31,000 x g for 15 min at 4°C, and the pellet was resuspended in ice-cold 10 mM Tris-HCl (pH 7.4) to a protein concentration of 15–20 mg/ml, as determined by method of Lowry using BSA as standard. Binding assay with [3H]DTG and [3H](+)-pentazocine were carried out as described previously, using 200–250 µg of membrane protein per tube in a final volume of 250 µl. Scatchard plots of both radioligands were carried out using a combination of radiolabeled and unlabeled ligand to achieve a concentration range of 1–400 nM for [3H]DTG and 0.1–1000 nM for [3H](+)-pentazocine.
Competition Binding Studies of [125I]PIMBA in Human Prostate Cancer Cells (DU-145).
The affinity of compounds tested for sites labeled by radiolabeled [125I]PIMBA was determined by cell binding assays. The in vitro binding assays were carried out with DU-145 prostate tumor whole cells as follows. The medium from T75 tissue culture flasks were decanted, and cells were scraped using a cell scraper and suspended in RPMI 1640 (1 x mod) with glutamine medium (Cellgro, Herndon, VA). The cells suspension was centrifuged for 5–6 min on a Sorvall RT6000B refrigerated centifuge at 2000 rpm for 5 min. The medium was decanted and the cells were suspended again in RPMI 1640 (1 x mod) with glutamine medium without serum. An aliquot of the cell (50,000–100,000 cells) suspension was incubated with the radiopharmaceutical (0.05 nM) and the increasing concentrations (1.0 nM to 100 µM) of competing sigma ligands. The total volume was kept constant at 1.0 ml with the medium, and the suspension was incubated at 37°C for 1 h. At the end of this period, the cell suspension was filtered through a Brandel cell harvester (Brandel, Gaithersburg, MD) and washed twice. The activity associated with the cells on filters was counted using PackardGamma counter. The data were analyzed by GraphPad InPlot 4 program (GraphPad Software) using nonlinear regress analysis.
Biodistribution Studies in Nude Mice Bearing Human Prostate Tumor (DU-145) Xenograft
BALB/c nude mice (18–25 g) rats were injected with a suspension of 5.0–9.0 million DU-145 cells in 0.2–0.3 ml of saline in the right flank of animals. The animals were housed in a pathogen-free temperature-controlled isolation room, and the diet consisted of autoclaved rodent chow and autoclaved water given ad libitum. After 3 weeks, palpable tumors were observed in 90% of injected animals. The animals were anesthetized with ketamine/xylazine and injected i.v. with [125I]PIMBA or 2-[125I]BP or 4-[125I]PAB (7–12 µCi) in 0.3 ml of saline containing 10% ethanol solution. At 1, 6, and 24 h postinjection, blood samples were drawn by cardiac puncture, and the nude mice were sacrificed thereafter by cardiectomy while under ketamine/xylazine anesthesia. The organs of interest and the tumors were then excised, blotted with tissue paper, and weighed, and the radioactivity was counted. The %ID per organ was determined by comparison of the tissue radioactivity with suitably diluted, known quantity aliquots of the injected dose. The results of biodistribution studies are summarized in Tables 1
2
3
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RESULTS AND DISCUSSION |
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. 2-IBP and radioiodinated 2-[125I]BP were synthesized using a procedure described in the literature (24)
. Similarly, 4-IPAB and radioiodinated 4-[125I]PAB were synthesized as described previously (14)
. The synthesis of nonradioactive PIMBA involved the condensation of 4-methoxybenzoyl chloride with 2(1-piperidine)ethylamine in the presence of triethylamine. The resulting benzamide was iodinated using electrophilic thallation (23)
. Pharmacological characterization of 2-IBP and 4-IPAB have been reported previously (14
, 16)
Receptor binding affinity for PIMBA was carried out for sigma-1 receptor sites in guinea pig brain membranes using [3H](+)-pentazocine. Its affinity for sigma-2 sites was determined in rat liver membranes using [3H]DTG in the presence of dextrallorphan. PIMBA exhibited a high affinity for sigma-1 sites (Ki = 11.8 nM) and a modest affinity for sigma-2 sites (Ki = 206 nM; Table 4
). Similarly, 4-IPAB and 2-IBP also displayed a high affinity for sigma-1 receptor subtype, showing Kis of 2.57 and 1.64 nM, respectively. 2-IBP was also found to have a high affinity for sigma-2 sites (Ki = 29.6 nM) whereas 4-IPAB had a modest affinity for sigma-2 subtypes (205 nM). Thus, all three radioligands evaluated for their potential to image prostate cancer in this study had a high affinity for sigma-1 receptor subtype (1–15 nM). 2-IBP had a high affinity for sigma-2 sites as well.
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). The specific activity of [125I]PIMBA ranged from 1850 to 2030 (Ci/mmol), as determined by HPLC. Similarly, radioiodinated 4-[125I]PAB and 2-[125I]BP were also prepared in high yield and with high specific activities, as reported previously (14
, 24)
.
We had earlier reported the binding characteristics of 2-[125I]BP in DU-145 prostate tumor cells and showed that the binding curve was curvilinear, indicating binding to the multiple sites (24)
. Here, we investigated the in vitro binding characteristics of [125I]PIMBA to DU-145 cells. A high degree of specific binding was observed in the cells that were in proliferating stages of cell cycle (2–4 days postsplit). Four different classes of sigma ligands were used for competition studies, i.e., three benzamides (PIMBA, 4-IBP, and 4-IPAB), one arylethylenediamine (BD1008), one butyrophenone (haloperidol), and a benzenesulfonamide (N-[2-(1'-piperidinyl)-ethyl]4-iodobenzenesulfonamide). The inhibition of specific binding of [125I]PIMBA was found to be dose dependent for all six sigma receptor-binding agents studied. Kis for various competing ligands are listed in Table 5
. The rank order of potency for various sigma receptor binding ligands for competition at sites labeled by [125I]PIMBA was found to be: (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD1008) > PIMBA > haloperidol > 4-IPAB and N- [2-(1'-piperidinyl)ethyl]4-iodobenzenesulfonamide. It is apparent from the plots that the binding data fits a two-site model better than a one-site model. Fig. 3
shows representative examples of nonlinear regression fit for both one-site and two-site fits. This finding is not surprising in the light of our previous results in DU-145 cells and also in various breast cancer cells (T47D and MCF-7), whereby curvilinear plots were obtained when various radioiodinated benzamides were competed against sigma ligands. These results indicated that radioiodinated ligand [125I]PIMBA binds to multiple sites present on human prostate tumor cells. This finding has significant implications for diagnostic and therapeutic application of cancer for various sigma receptor binding ligands. Similar findings were also reported for somatostatin receptors that are expressed on a variety of human tumors also (25)
. Multiple binding sites were reported for the binding of 123I-labeled octreotide against unlabeled peptides in primary carcinoid tumors. The expression of sigma-1 and sigma-2 sites was further confirmed by Scatchard analysis using [3H](+)-pentazocine, a highly selective sigma-1 ligand. Kd for sigma-1 site was found to be 5.80 ± 1.3 nM (r = 0.966), and Bmax was 1800 ± 117 fmol/mg of protein. A representative Scatchard plot is shown in Fig. 1
. Similarly, the dissociation constant (Kd) for sigma-2 binding site using [3H]DTG in the presence of dextrallorphan was found to be 15.71 ± 3.6 nM. A high density of sigma-2 sites was found (Bmax = 1930 ± 176 fmol/mg protein). The total amount of sigma-1 and sigma-2 binding sites (3700 fmol/mg of protein) translates to 1.8 million sigma receptors/cell. This number is one logarithmic scale higher than somatostatin and VIP receptors expressed on human tumors (26)
. Therefore, sigma receptors are very attractive targets for diagnostic/therapeutic oncological applications.
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2
3)
. As expected, all three radioiodinated benzamides showed hepatic and bowel uptakes. There were, however, remarkable differences in the liver uptake and retention of the three compounds. 2-[125I]BP and 4-[125I]PAB had a high uptake (8%ID/g) at 1 h postinjection, and [125I]PIMBA had a very low liver uptake (1.12%ID/g). Similarly, lung and kidney uptake of radioactivity was also high for 2-[125I]BP and 4-[125I]PAB but relatively low for [125I]PIMBA. Stomach and bowel activity (total, 35%ID/g) was very high for 2-[125I]BP, presumably due to its higher lipophilicity due to the presence of benzyl group. [125I]PIMBA showed much lower amounts of radioactivity in stomach and bowel (total, 5% ID/g). This uptake may be attributed in part to the lipophilicity of drug, receptor-bound fraction, and also nonspecific binding. The uptake of activity in tumor was observed to be very high for 2-[125I]BP (6.63%ID/g) at 1 h postinjection and modest uptake for 4-[125I]PAB and [125I]PIMBA was observed 2.2 and 1.34%ID/g, respectively. The higher uptake of 2-[125I]BP at one and six h postinjection may be due to higher high affinity of 2-IBP for sigma-2 subtypes (29 nM), as compared with low affinities of 4-IPAB and PIMBA for sigma-2 subtypes. Tumor:muscle ratios were high for all three compounds at 1 h postinjection; however, at 6 h postinjection, tumor:muscle and tumor:blood ratios were very high for [125I]PIMBA. Therefore, of the three compounds studied, [125I]PIMBA appeared to be most promising. Another important factor in imaging prostate carcinoma is the excretion of radioactivity from the bladder. There was a significant release of radioactivity in the bladder for 2-[125I]BP, followed by [125I]PIMBA and 4-[125I]PAB. These results indicated that tumor uptake and retention of three radioiodinated benzamides studied here look promising and tumor to blood and tumor to muscle ratios are high enough at early time points for visualization of prostate tumors. Our recent studies in vitro cell binding studies using radioiodinated sigma receptor ligand, 4-[125I]iodo-N-[2-(1'-piper-idinyl)ethyl]benzamide, 4-[125I]PAB showed that 4-[125I]PAB had a higher specific binding in breast cancer cells (T47D and MCF-7) and also in human prostate tumor (DU-145) cells when the cells were in logarithmic-phase growth than those at quiescent stages. The stimulation of mitosis with insulin or 10% serum resulted in higher binding of sigma ligand 4-[125I]PAB. These results imply that sigma binding ligands could be useful for non invasive scintigraphic imaging of proliferating tumors and also in monitoring the progress of chemotherapy (28)
. Furthermore, support of imaging proliferating tumors was shown in vitro binding studies by others (29)
. We have recently designed several radioiodinated ligands that bind to sigma receptors in tumor cell cultures in vitro and in several animal models possessing human tumor xenografts. Further studies in patients with metastatic prostate carcinoma are required to confirm the validity of these preclinical results.
On the basis of these pharmacokinetic findings and the kinetics of tumor uptake and retention, we decided to study the antiproliferative activity of PIMBA in different prostate tumor cell lines. Sigma agonists have been shown to induce apoptosis in a variety of human neural tumor (SK-N-SH) cells (30)
. In this study, the antiproliferative/antineoplastic activity of PIMBA was determined in various human prostate tumor cell colonogenic assays. The results indicated that there was a significant decrease in the number of colonies formed, when treated with 10 µM PIMBA, for all three prostate cell lines (androgen-dependent and androgen-independent) as compared with the control. DU-145 and LNCaP seemed to exhibit the maximum response (80% colonies death) in vitro assays (Table 6)
. Furthermore, a dose escalation study was performed with PIMBA on DU-145 and PC-3 cells. A dose-dependent inhibition of colony growth formation was observed (Table 7)
. On the basis of acute i.v. toxicity in Sprague Dawley rats and rabbits for IPAB, LD50 was found to be 110 mg/kg.4
It is concluded from these results that the in vivo toxicity of the iodobenzamides evaluated may be very low, whereas in vitro cytotoxicity is modest. Because a significant cytotoxicity was observed only at higher concentrations, the cytotoxic effect may or may not be mediated by the sigma receptor. These results suggest that sigma receptor binding ligands would not be only useful for in vivo receptor diagnostic imaging or targeted radiotherapy but may also play an important role in targeting various malignancies as chemotherapeutics.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by National Cancer Institute Grant CA 58496 and by Research Corporation Technologies (Tucson, AZ). 
2 To whom requests for reprints should be addressed, at 2300 I Street NW, 530 Ross Hall, Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037. Phone: (202) 994-5031; Fax: (202)994-8974; E-mail: radcsj{at}gwumc.edu
3 The abbreviations used are: DTG, 1,3-di-o-tolylguanidine; PIMBA, N-[2-(1'-piperidinyl)ethyl]-3-iodo-4-methoxybenzamide; HPLC, high-performance liquid chromatography; 2-[125I]BP, 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide; 4-[125I]PAB, 4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide; %ID, percentage injected dose; 2-IBP, N-(N-benzylpiperidin-4-yl)-2-iodobenzamide; 4-IPAB, N-[2-(1'-piperidinyl)ethyl]4-iodobenzamide.
Received 1/29/99. Accepted 7/16/99.
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