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Experimental Therapeutics |
-2b and Docetaxel
Departments of Urology [S. F. H., T. K., D. K., P. S., B. M., D. S., C. P. N.] and Cancer Biology [S. J. K., C. B., D. F., I. J. F., J. J. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2b (PEG-IFN--2b) and docetaxel could represent a two-compartment targeting of primary tumor (tumor cells and tumor-associated endothelial cells) and inhibition of regional lymph node metastasis. The antiangiogenic properties of IFN were combined with the cytotoxic properties of docetaxel, resulting in apoptosis of both tumor cells and endothelium and hence significant inhibition of primary tumor growth. We first determined the optimal biological dose of PEG-IFN--2b (70,000 IU/week) necessary to down-regulate the expression of basic fibroblast growth factor, matrix metalloprotease-9, and matrix metalloprotease-2. The therapeutic dose of docetaxel (10 mg/kg/week) was determined by efficacy and minimal body weight loss. Therapy beginning 3 days after orthotopic implantation of PC3-MM2 prostate cancer cells reduced tumor weight by 37% in mice treated with PEG-IFN--2b, by 60% in mice treated with docetaxel, and by 83% in those given both drugs. PEG-IFN--2b also induced apoptosis of tumor-associated endothelial cells and hence a significant decrease in microvessel density. Our data indicate that the combination of PEG-IFN- and docetaxel inhibits neoplastic angiogenesis by inducing a decrease in the local production of proangiogenic molecules by tumor cells, resulting in increased apoptosis of tumor-associated endothelial cells. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and IFN-ß directly inhibit the proliferation of tumor cells of different histological origins (1, 2, 3, 4)
. Recent studies indicate that IFN- and IFN-ß can also down-regulate the expression of proangiogenic molecules, such as bFGF2
(5, 6, 7)
, IL-8 (8
, 9)
, and the metalloproteases, MMP-2 and MMP-9 (10, 11, 12)
, and activate host effector cells (4
, 13)
.
For therapy of human bladder carcinoma grown in athymic nude mice, the optimal biological dose (i.e., the dose that exerts a maximal antiangiogenic effect) is a relatively low dose, e.g., 10,000 units administered on a daily schedule (7)
. Pharmacokinetic studies have demonstrated that the half-life of IFNs in the circulation of patients is on the order of minutes (14)
, thus making therapeutic levels difficult to sustain, which may in turn compromise the effectiveness of IFN in the therapy of solid tumors (14
, 15)
. Pegylation of IFN is a biochemical method of delaying clearance and reducing immunogenicity (16)
and consists of a straight-chain polyethylene glycol moiety conjugated to IFN--2b. Therapeutic levels can be maintained through once weekly dosing (17)
. For example, recent clinical trials have shown that PEG-IFN- is significantly more effective than free-form IFN- in the treatment of chronic hepatitis C (18
, 19)
, and differences in clinical outcome have been related to the ability of pegylation to sustain absorption, restrict the volume of distribution, and reduce clearance of IFN- (19)
.
We evaluated the therapeutic effect of PEG-IFN--2b in combination with docetaxel against the metastatic human prostate cancer PC3-MM2 implanted in the prostates of athymic nude mice. The growth and metastatic potential of PC3-MM2 is dependent upon its secretion of proangiogenic factors bFGF, VEGF, MMP-9, and IL-8 (20)
. Because IFN- down-regulates the expression of these factors in different human tumors (5, 6, 7, 8, 9, 10
, 12)
and because the microtubule destabilizer docetaxel is currently being evaluated in clinical trials against advanced prostate cancer (21, 22, 23, 24)
, we hypothesized that a combination therapy for prostate cancer using the antiangiogenic properties of IFN- together with the cytotoxic properties of docetaxel might result in a potent two-compartment attack (via the tumor vasculature and tumor cells) upon the growth and metastasis of prostate cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mice.
Male NCr-nu/nu nude mice were obtained from the Animal Production Area of the National Cancer Institute-Frederick Cancer Research Facility (Frederick, MD). The mice were maintained under specific pathogen-free conditions in facilities approved by the American Association for Accreditation of Laboratory Animal Care and in accordance with current regulations and standards of the United States Department of Agriculture, United States Department of Health and Human Services, and the NIH. The mice were used according to institutional guidelines when they were 8–10 weeks of age.
Orthotopic Implantation of Tumor Cells.
To produce prostate tumors, subconfluent cultures of PC3-MM2 cells were given fresh medium 24 h before being harvested by a brief treatment with 0.25% trypsin and 0.02% EDTA. Trypsinization was stopped with medium containing 10% fetal bovine serum, and the cells were washed once in serum-free medium and resuspended in HBSS. Only single-cell suspensions with a viability of >90% were used for injections. Mice anesthetized with an i.p. injection of nembutal were placed in a supine position. A lower midline abdominal incision was made, the prostate was exteriorized, and tumor cells (5 x 104/0.05 ml HBSS) were injected into the right lobe of the prostate. A well-localized bleb was a sign of a technically satisfactory injection. The abdominal incision was closed in one layer using metal clips.
Determination of Optimal Biological Dose of Human PEG-IFN--2b and Therapeutic Dose of Docetaxel.
Three days after implantation of PC3-MM2 cells, groups of mice were randomized to receive different doses of s.c. PEG-IFN--2b (Schering-Plough Corp., Kenilworth, NJ; specific activity, 6 x 107 IU/mg). Twenty-three days after orthotopic implantation of tumor cells, five mice from each group were killed, and their prostates were removed and processed for immunohistochemical analysis. The remaining mice were killed at 4 weeks. The primary prostate tumors were weighed, and the metastasis to regional lymph nodes was determined. Other groups of mice were randomized to receive different doses of docetaxel (Aventis, Paris, France). Docetaxel was administered weekly by i.p. injection of either 2.5, 5, or 10 mg/kg. Vehicle was used as a control. The mice were killed at 4 weeks, and the extent of prostatic tumor burden was determined.
Systemic in Vivo Therapy with Combination Docetaxel and PEG-IFN--2b.
Mice were randomized into the following groups 3 days after implantation of tumor cells: saline (control); docetaxel administered i.p. once weekly (10 mg/kg); PEG-IFN--2b s.c., administered weekly (70,000 IU); or the combination of these two therapies. Treated mice were killed when moribund (5–6 weeks), and the weight of the primary prostate tumors and the incidences of regional (pelvic and paraaortic) lymph node metastasis were recorded. Histopathology confirmed the nature of the disease. For immunohistochemical and histological staining procedures, one part of the tumor tissue was fixed in formalin and embedded in paraffin. Another part of the tumor was embedded in OCT compound (Miles, Inc., Elkhart, IN), snap-frozen in liquid nitrogen, and stored at -70°C.
ELISA for Serum bFGF.
The level of bFGF protein in the serum was measured by the Quantikine ELISA kit (R&D Systems, Minneapolis, MN). The minimal level of bFGF detectable by this assay is 1 pg/ml.
Immunohistochemical Determination of bFGF, MMP-9, VEGF, IL-8, E-Cadherin, PCNA, and CD31.
Paraffin-embedded tissues were used for identification of bFGF, MMP-9, VEGF, IL-8, E-cadherin, PCNA, and CD31. Sections (4–6 µm thick) were mounted on positively charged Superfrost slides (Fisher Scientific, Houston, TX) and dried overnight. Sections were deparaffinized in xylene, followed by treatment with graded series of alcohol [100, 95, and 80% ethanol/double-distilled H2O (v/v)] and rehydrated in PBS (pH 7.5). Sections analyzed for PCNA were microwaved 5 min for "antigen retrieval" as described previously (26)
. All other paraffin-embedded tissues were treated with pepsin (Biomeda) for 15 min at 37°C and washed with PBS. Frozen tissues used for identification of CD31 were sectioned (8–10 µm), mounted on positively charged Plus slides (Fisher Scientific), and air dried for 30 min. Frozen sections were fixed in cold acetone (5 min), acetone/chloroform (v/v; 5 min), and acetone (5 min) and washed with PBS. Immunohistochemical procedures were performed as described previously (27, 28, 29, 30, 31)
. A positive reaction was visualized by incubating the slides with stable 3,3'-diaminobenzidine for 10–20 min. The sections were rinsed with distilled water, counterstained with Gill’s hematoxylin for 1 min, and mounted with Universal Mount (Research Genetics). Control samples exposed to secondary antibody alone showed no specific staining.
Immunofluorescence Double Staining for Apoptotic Endothelial Cells.
Frozen tissues were sectioned (8–10 µm), mounted on positively charged slides, air dried for 30 min, and fixed in cold acetone for 5 min, acetone/chloroform (v/v) for 5 min, and acetone for 5 min. Samples were washed three times with PBS, incubated with protein-blocking solution containing 5% normal horse serum and 1% normal goat serum in PBS for 20 min at room temperature, and incubated with an appropriate dilution (1:400) of rat monoclonal antimouse CD31 antibody (PharMingen, San Diego, CA) over 18 h at 4°C. Next, the samples were rinsed four times 3 min each time with PBS and then incubated with an appropriate dilution (1:200) of secondary goat antirat conjugated to Texas Red for 1 h at room temperature in the dark. Samples were washed twice with PBS containing 0.1% Brij and once with PBS for 5 min.
Apoptosis was detected using TUNEL was performed using a commercially available apoptosis detection kit (Promega Corp., Madison, WI) with the following modifications (32) . Samples were fixed with 4% paraformaldehyde (methanol-free) for 10 min at room temperature, washed twice with PBS for 5 min, and then incubated with 0.2% Triton X-100 for 15 min at room temperature. After two washes of 5 min each with PBS, the samples were incubated with equilibration buffer (from the kit) for 10 min at room temperature. The equilibration buffer was drained, and reaction buffer containing equilibration buffer, nucleotide mix, and terminal deoxynucleotidyl transferase enzyme was added to the tissue sections and incubated in a humid atmosphere at 37°C for 1 h in the dark. The reaction was terminated by immersing the samples in 2x SCC for 15 min. Samples were washed three times for 5 min to remove unincorporated fluorescein-dUTP. For quantification of endothelial cells, the samples were incubated with 300 µg/ml of Hoechst stain for 10 min at room temperature. Fluorescence bleaching was minimized by mounting slides with glycerol/PBS mounting media containing 0.1 M propyl gallate (Sigma Chemical Co., St. Louis, MO). Immunofluorescence microscopy was done on a Zeiss Axioplan fluorescence microscope (Carl Zeiss, Inc., Thornwood, NY) equipped with 100 W HBO mercury lamp and narrow bandpass excitation filters (Chrom Technology Corp., Brattleboro, VT) to individually select for green, red, and blue fluorescence. Images were captured with a cooled CCD Hamamatsu C5810 camera (Hamamatsu Photonics K.K., Bridgewater, NJ) and Optimas software (Media Cybernetics, Silver Spring, MD) on a Dell computer (Round Rock, TX). Composite photographs were made using Adobe Photoshop software (Adobe Systems, Mountainview, CA). Endothelial cells were identified by red fluorescence, and DNA fragmentation was detected by colocalized green fluorescence within the nuclei of apoptotic cells resulting in a yellow fluorescence. For the quantification of total TUNEL expression, the number of apoptotic events was counted in 10 random 0.159-mm2 fields at x100.
Quantification of MVD and PCNA.
To quantify MVD and PCNA, 10 random 0.159-mm2 fields at x100 were captured for imaging within tumor tissue.
Statistical Analysis.
In vivo results were compared using the unpaired Student’s t test and using the Mann Whitney U test. The incidence of lymph node metastasis was compared by using the 
2 test. In vitro protein expression by ELISA was compared using the unpaired Student’s t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2b or Docetaxel against PC3-MM2 Cells.-2b (0–1000 IU/ml) or docetaxel (0–100 ng/ml). Growth inhibition of the cultured tumor cells by PEG-IFN--2b was <30% at the highest concentration. Hence, this cell line is relatively resistant to the antiproliferative effects of PEG-IFN--2b. The IC50 of docetaxel was determined to be 2.3 ng/ml (data not shown).
Inhibition of Prostate Carcinoma Growth and Metastasis by PEG-IFN--2b: Determination of Optimal Biological Dose.
The prostates of nude mice were injected with PC3-MM2 cells on day 0. Three days later, the mice were randomized into four groups and received therapy consisting of once weekly s.c. injections of either sterile saline (control) or PEG-IFN--2b at a dose of 35,000 IU, 70,000 IU, or 350,000 IU. All mice were killed on day 35. Detailed necropsy revealed that all of the mice had tumors in the prostate, except for one mouse each in the 35,000 IU and the 70,000 IU treatment groups. As shown in Table 1
, therapy with PEG-IFN--2b at all three doses significantly decreased median tumor when compared with the control (1007, 511, 759, and 1370 mg, respectively). Moreover, the use of PEG-IFN--2b at the optimal biological dose of 70,000 IU resulted in a greater decrease in primary tumor weight than that observed using 35,000 IU or 350,000 IU. Thus, the therapeutic effect of PEG-IFN--2b was biphasic. Histologically positive regional lymph nodes were found in 100% of control mice and in 100% of the mice treated with PEG-IFN--2b at the low dose of 35,000 IU weekly. However, treatment with either 70,000 IU or 350,000 IU or PEG-IFN--2b resulted in a significant reduction in the incidence of lymph node metastasis from 100% in control mice to 22 and 30%, respectively.
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-2b.-2b as described above (35,000, 70,000 or 350,000 IU/week). All mice were killed on day 23. Tumors harvested from the different groups were processed for histology and stained for the presence of bFGF, MMP-9, MMP-2, and VEGF. Tumors from mice treated with PEG-IFN--2b demonstrated decreased expression of these proangiogenic molecules (Fig. 1)
. Treatment with 70,000 IU/week resulted in the lowest expression of bFGF, MMP-9, and MMP-2 as determined by quantitative imaging. There was no difference in expression of VEGF and IL-8. Moreover, treatment of mice with PEG-IFN--2b at 70,000 IU/week resulted in a significant decrease in the MVD of tumors as compared with the control (16 ± 8.6 and 47 ± 6.8, respectively). Tumors from mice treated with 35,000 IU/week and 350,000 IU/week also demonstrated a lower mean MVD (35.6 ± 9.9 and 36.2 ± 7.5) versus control; however, these differences were not significant.
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Inhibition of Prostate Carcinoma Growth and Metastasis by Docetaxel and Determination of Maximal Tolerated Dose.
We determined the therapeutic dose of docetaxel to be used as a single agent or in combination therapy. Results are also shown in Table 1
. Athymic nude mice received intraprostatic injections of PC3-MM2 cells. Three days later, the mice were randomized into four groups for treatment with either docetaxel at 2.5, 5, or 10 mg/kg/week or diluent as a control. All mice were killed on day 32 after tumor cell injection. Detailed necropsy revealed that each group had 2 mice that did not have primary prostate tumors. Weekly i.p. injections of docetaxel at all doses significantly decreased median tumor weight when compared with the control (776, 483, 457, and 1286 mg, respectively). There were no significant differences between the groups of treated mice, although the lowest median tumor weight was observed at the highest dose of 10 mg/kg. However, a significant reduction in the incidence of histologically positive regional lymph nodes was found in the 5 and 10 mg/kg/week docetaxel treatment groups when compared with the control.
Combination Therapy of Orthotopic Prostate Cancer by Docetaxel at 10 mg/kg/Week and PEG-IFN--2b at 70,000 IU/Week.
Athymic nude mice received intraprostatic injections of PC3-MM2 cells, and 3 days later, the mice were randomized into four treatment groups. The first group received weekly i.p. injections of docetaxel at 10 mg/kg, the second group received weekly s.c. injections of PEG-IFN--2b, the third group received the combination therapy, and the last group received vehicle only. All mice were killed on day 42 after tumor cell injection. Detailed necropsy revealed that tumors were present in the prostate in 12–13 of the 15 mice/group. The data summarized in Table 2
show that weekly therapy with either docetaxel, PEG-IFN--2b, or the combination significantly decreased prostatic tumor weight when compared with the control (710, 1121, and 1786 mg, respectively). In addition, combination therapy resulted in a greater reduction of tumor burden than the use of either agent alone (P < 0.008). Histologically positive regional lymph node metastases were found in 10 of 12 control mice, 1 of 12 mice treated with docetaxel, 6 of 13 mice treated with PEG-IFN--2b, and 1 of 12 mice given combination therapy. Hence, the metastatic spread of primary tumor appeared to be limited by therapy with docetaxel.
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. All tumors contained necrotic zones and a large number of infiltrating cells in their central portions. Protein expression was assessed only at the periphery of the tumors in areas not containing necrosis. Immunohistochemistry using specific anti-bFGF and anti-MMP-9 antibodies demonstrated that when compared with controls, tumors treated with docetaxel alone expressed similar levels of these markers, whereas tumors treated with PEG-IFN--2b or PEG-IFN--2b plus docetaxel expressed decreased levels. Immunohistochemistry using specific anti-MMP-2 antibodies demonstrated that, when compared with controls, tumors treated with docetaxel alone or PEG-IFN--2b alone expressed similar levels of these markers. Lastly, immunohistochemistry using specific anti-E-cadherin antibodies demonstrated that tumors from mice with treated with docetaxel alone expressed similar levels of these markers, whereas tumors from mice treated with PEG-IFN--2b or combination therapy had increased staining for this cellular protein.
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and Table 3
. The median number of PCNA-positive tumor cells in control tumors was 581. After therapy with docetaxel alone or docetaxel plus PEG-IFN--2b, this number decreased to 385 and 284, respectively (P < 0.01). Treatment with PEG-IFN--2b alone did not result in a significant reduction in cell proliferation when compared with the control (515 and 581, respectively).
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-2b-treated animals, 5; and in tumors from mice given combination therapy, 11.5 (P < 0.005).
MVD (measured by staining antibodies against CD31) was directly proportional to expression of bFGF. Tumors from control mice contained an average of 19.5 blood vessels/high-power field. MVD was not significantly reduced in tumors of mice treated with docetaxel (15.5) but was in tumor of mice treated with PEG-IFN--2b alone or combination therapy (8.4 and 6.5, respectively; P < 0.003).
Finally, apoptosis of endothelial cells within tumors was determined by using a method for simultaneously labeling markers for CD31 and apoptosis (TUNEL). Whereas tumors treated with PEG-IFN--2b or combination therapy contained apoptotic endothelial cells, tumors in control mice and in mice treated with docetaxel as a single agent did not (yellow reaction, Fig. 3
)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2b on tumor cells were established by molecular techniques that demonstrated a decrease in synthesis and secretion of bFGF and a decrease in expression of MMP-9, genes that correlate with growth and metastasis of prostate cancer (20)
. The PC3-MM2 cells used in our study are resistant to the antiproliferative effects of PEG-IFN--2b, and reduction in tumor burden appears to be solely attributable to reduction of proangiogenic gene expression. Treatment of a variety of human cancer cell lines have demonstrated the ability of IFN- to down-regulate proangiogenic factors such as bFGF, IL-8, MMP-9, and MMP-2 (5
, 7, 8, 9
, 11
, 12)
. Our use of pegylated IFN- paralleled the results observed in the treatment of orthotopic human bladder cancer or liver metastasis of human colon cancer in nude mice with free-form IFN- (33
, 34)
. The results presented here demonstrate that therapeutic effects can also be achieved by systemic low-dose administration of PEG-IFN--2b.
The rationale for the use of chronic, low-dose IFN- has been exemplified in its use as therapy for infantile hemangiomas (35, 36, 37, 38)
. It has been shown recently that the antiangiogenic properties of IFN- may be the basis of regressions observed in Kaposi’s sarcoma and the effect of IFN-ß on murine leukemia and melanoma (39, 40, 41, 42)
. Similar to melanoma, renal cell carcinoma, and transitional cell carcinoma, metastatic prostate carcinoma has also been treated with IFN- in clinical trials (21
, 43, 44, 45)
. However, responses in these trials have been modest, and the optimal biological dose has yet to be determined. This inability to achieve an optimal therapeutic use of high-dose IFN- may be attributable to the induction of a recently described family of proteins that negatively regulate cytokine signaling (46
, 47)
. IFN signaling is mediated by JAK receptor-associated tyrosine kinases and latent cytoplasmic transcription factors called STATs (48)
. Suppressors of cytokine signaling (SOCS) negatively regulate IFN signaling through inhibition of the JAK/STAT pathway (46
, 49
, 50)
. Although the inhibition of STAT3 activation by SOCS3 is well described (51
, 52)
, the relationship between maximal tolerated doses of IFN- used in clinical trials and the induction of down-regulation of STAT1 signaling has yet to be fully elucidated.
Treatment of tumor cells with IFN has been shown recently to up-regulate the expression of E-cadherin, a cell-surface molecule involved in the cohesive properties of cells within tissue (53)
. Indeed, the relative expression of E-cadherin (a measure of the cohesive properties of tumor) and of metalloproteases, such as MMP-9 (a measure of the invasive properties of tumor), correlates with and predicts the metastatic potential of a variety of primary cancers, including those of the prostate, bladder, colon, pancreas, and lung. It has been shown that the higher the ratio of MMP-9:E-cadherin, which reflects the loss of E-cadherin as well as abundant expression of the enzyme(s) used by invasive tumor cells, the higher the risk of metastasis (30
, 31
, 54
, 55)
. In our present study, we observed inhibition of the expression of MMP-9 and an up-regulation of E-cadherin after therapy with PEG-IFN--2b, suggesting that the significant reduction in the incidence of lymph node metastasis was attributable to administration of IFN-.
Paclitaxel and docetaxel are currently being evaluated in advanced prostate cancer (21, 22, 23, 24)
. The strong cytotoxic effect of docetaxel combined with the antiangiogenic effect of PEG-IFN--2b resulted in inhibition of metastasis to the regional lymph nodes.
The use of conventional cytotoxic therapies (chemotherapeutics and irradiation) together with inhibitors of angiogenesis represents a powerful approach to cancer therapy. The results presented here complement other studies that have shown endothelial cell apoptosis resulting from removal of proangiogenic factors in the microenvironment of the tumor, which may sensitize endothelial cells to the effects of chemotherapy. Several reports have demonstrated that blockade of growth factor receptors in combination with chemotherapy results in apoptosis of tumor-associated endothelium (32
, 56
, 57)
. In conclusion, our studies demonstrated that biological doses of PEG-IFN--2b produce significant antiangiogenic effects, and they expand the preclinical rationale for use of cytotoxic therapeutics in combination with inhibitors of angiogenesis.
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at University of Texas M. D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston, Texas 77030. 
2 The abbreviations used are: bFGF, basic fibroblast growth factor; IL, interleukin; MMP, matrix metalloprotease5; MVD, microvessel density; PCNA, proliferating cell nuclear antigen; VEGF, vascular endothelial growth factor; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; STAT, signal transducer and activator of transcription.
Received 4/25/02. Accepted 8/28/02.
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