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Keywords:

  • docetaxel;
  • prostate-specific antigen;
  • neoadjuvant systemic therapy;
  • prostatic carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

The objective of the current study was to determine the histologic and molecular changes that occurred in patients with high-risk, localized prostate cancer (PCa) after neoadjuvant docetaxel chemotherapy.

METHODS.

Patients who had locally advanced PCa (serum preoperative [initial] prostate-specific antigen [iPSA] level ≥15 ng/mL, or clinical ≥T2b disease, or biopsy Gleason score [GS] ≥8) and no evidence of metastatic disease received 6 doses of intravenous docetaxel (40 mg/m2) administered weekly for 6 weeks followed by radical prostatectomy (RP). The Wilcoxon signed-rank test was used to compare pretreatment and posttreatment markers.

RESULTS.

Twenty-eight patients completed chemotherapy and underwent RP at the Cleveland Clinic; none achieved a pathologic complete response. Pretreatment diagnostic prostate biopsies (PBx) were reviewed in all patients, and unstained sections of formalin-fixed tissue were available from 11 patients. The median patient age was 62 years (range, 49–72 years), and the median iPSA was 6.8 ng/mL (range, 2.5–24 ng/mL). At a median follow-up of 49.5 months (range, 23–72 months), 12 patients (43%) remained clinically and biochemically free of disease with no additional therapy, and 16 patients (57%) had biochemical failure. The pretreatment GS was 6 in 2 patients (7%), 7 in 10 patients (36%), 8 in 11 patients (39%) and 9 in 5 patients (18%). Two patients (7.1%) had organ-confined disease, and 23 patients (82.1%) had extraprostatic extension. Four patients (14.3%) had positive lymph nodes, and 11 patients (39.3%) had seminal vesicle involvement. Immunohistochemical (IHC) staining for a panel of markers involved in various cellular functions (α-methylacyl-coenzyme A racemase [AMACR], β-tubulin I, β-tubulin III, cyclin D1, p27, p21, Ki-67, p53, Bcl-2, and an apoptosis detection kit [ApopTag]) was performed on a tissue microarray that contained the posttreatment (RP) tissue specimens and on the PBx specimens, if available. When the IHC staining patterns were compared between PBx and RP specimens using the Wilcoxon signed-rank test, only p53 expression (P = .017) and Bcl-2 expression (P = .014) were found to be increased significantly after neoadjuvant docetaxel treatment. However, after performing the Bonferroni adjustment, these differences were no longer significant (P > .005). Ki-67, ApopTag, β-tubulin I, and β-tubulin III expression levels also were increased after treatment; however, the differences were not found to be statistically significant. The expression levels of AMACR, p27, p21, and cyclin D1 were comparable in pretreatment and posttreatment specimens.

CONCLUSIONS.

The current results indicated that, although it will require longer follow-up studies and larger numbers of patients to ascertain the value of neoadjuvant treatment, the negative findings of the current study may explain the lack of clinical response in patients who received neoadjuvant docetaxel for PCa. Although the results were subject to interpretation limits based on the study size, the increased expression of p53 and Bcl-2 that was detected after treatment using the Wilcoxon signed-rank test suggested that the apoptotic pathway may be an important target for this drug, and further investigation is warranted. Cancer 2007. © 2007 American Cancer Society.

Prostate cancer (PCa) is the most commonly diagnosed nonskin malignancy and the third leading cause of cancer death in men.1 Patients who have locally advanced PCa have worse outcomes after radical prostatectomy (RP) compared with patients who have more favorable parameters. Although chemotherapy historically has had limited utility in treating PCa, the results from 2 recent randomized clinical trials indicated that docetaxel-based chemotherapy improves survival in patients with hormone-refractory PCa.2, 3 Given the demonstrated utility of docetaxel-based therapy in advanced disease, there has been considerable interest in exploring the utility of these agents in both the adjuvant and neoadjuvant settings in an attempt to improve systemic control of high-risk disease.

Docetaxel is a taxoid derived from the European yew tree, Taxus baccata. Taxanes (paclitaxel and docetaxel) achieve their antineoplastic activity by the stabilization of the microtubules with arrest in cell proliferation in the G2-M phase and by inducing Bcl-2 phosphorylation and inactivating antiapoptotic mechanisms.4 Drugs that affect the integrity of microtubules are able to induce Bcl-2 phosphorylation, abrogating the normal antiapoptotic function ofBcl-2 and initiating the apoptotic program in the cycling cancer cells. In this report, we describe the histologic and molecular characteristics of patients with locally advanced PCa who received neoadjuvant docetaxel.5

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients and Specimens

Twenty-nine patients were enrolled in this study between May 2001 and April 2003. Eligibility criteria included histologically documented, locally advanced PCa, which was defined by a serum preoperative (initial) prostate-specific antigen (iPSA) level ≥15 ng/mL; clinical tumor (T) classification T2b, T2c, or T3 (any PSA level or grade); or biopsy Gleason score (GS) ≥8 (any stage or PSA level); and no evidence of metastatic disease. The Cleveland Clinic Institutional Review Board reviewed and approved the trial in accordance with an assurance filed with and approved by the Department of Health and Human Services. All patients provided written informed consent before registration.

Treatment consisted of intravenous docetaxel at a dose of 40 mg/m2 administered weekly for 6 weeks. Within 3 weeks of completing chemotherapy, 28 of 29 patients underwent bilateral pelvic lymphadenectomy and retropubic RP according to a standardized technique under epidural anesthesia. After RP, patients were followed postoperatively by their urologists in a routine manner with serum PSA assessments every 3 to 6 months. Biochemical disease recurrence was defined as serum PSA levels ≥0.3 ng/dL on 2 occasions confirmed at least 1 week apart.5

The prostatectomy and lymphadenectomy specimens were fixed in formalin for 24 hours. The prostatectomy specimen was inked in 2 colors, step-sectioned at 3-mm intervals, and evaluated as quartermounts. The histologic analysis included evidence of residual cancer, necrosis, extraprostatic extension (EPE), seminal vesicle (SV) involvement, surgical margins, and lymph node status.

The pathologic response to the neoadjuvant treatment was assessed by a single pathologist (C.M.-G.). A pathologic complete response was defined as complete eradication of tumor.

Construction of Tissue Microarray and Collection of Pretreatment Specimens

A prostate tissue microarray (TMA) was constructed that contained samples from the 28 RP specimens, including PCa samples and corresponding nonneoplastic prostatic tissues as controls for each patient. Three different paraffin blocks from each patient were used to construct the TMA to ensure sampling from different PCa areas. Briefly, areas of interest (PCa and nonneoplastic tissue) were traced with a marker pen on hematoxylin and eosin-stained slides. The least differentiated regions of each individual paraffin-embedded prostate tumor were chosen. The corresponding areas were then marked on the corresponding paraffin blocks (donor blocks) and were arrayed precisely onto a new recipient paraffin block (35 × 20 mm) with a manual TMA arrayer (Beecher Instruments, Sun Praire, Wis). Three 1-mm-thick tissue cores from PCa and 3 nonneoplastic tissue cores were taken for each specimen. After the block construction was completed, 5-μm sections were cut with a microtome using an adhesive-coated tape-sectioning system (Instrumedics, Hackensack, NJ) and were mounted on Superfrost Plus glass slides and stored for future use. Hematoxylin and eosin staining was performed on the initial TMA slide to verify the histologic diagnosis for each core. The number of samples varied slightly between the individual marker analyses because of variability in the number of interpretable specimens on TMA sections.

Pretreatment diagnostic prostate biopsies (PBx) that were performed at other institutions were reviewed, and representative, unstained sections or corresponding paraffin blocks were requested after the patient's consent was obtained. Unstained PBx sections were available for only 11 of 28 patients (39%).

Immunohistochemistry

TMA and unstained PBx sections were used for immunohistochemistry (IHC) to analyze the expression of a panel of molecules involved in various cellular functions, such as proliferation (Ki-67), microtubule formation (β-tubulin I and β-tubulin III), apoptosis (Bcl-2, p53, p21, and an apoptosis detection kit [ApopTag]), cell cycle progression (cyclin D1, p27), and a potential early PCa marker, α-methylacyl-coenzyme A racemase (AMACR). A standard, indirect immunoperoxidase procedure (ABC-Elite; Vector Laboratories, Burlingame, Calif) was used for detection of the secondary antibodies. The primary antibodies, their dilutions, and the pretreatment conditions are listed in Table 1. Diaminobenzidine was used as chromogen in most of analyses except for β-tubulin III, for which alkaline phosphatase was used as the chromogen. The primary antibody was omitted for negative controls. All slides were read by a single pathologist (C.M.-G.). Quantification of the Ki-67 labeling index, p21, p27, Bcl-2, ApopTag, and p53 was performed by manually counting ≥1000 cells (for PBx sections) or the cells in all 3 cores that contained tumor (for TMA samples) and is expressed as the percentage of positive cells. For Ki-67 and p53 analyses, only nuclear staining was considered. The intensity of staining for AMACR, β-tubulin I, β-tubulin III, and cyclin D1 was scored visually and stratified into 4 groups: negative (−), weak (+), moderate (++), and strong (+++). For a marker to be considered positive, ≥5% of the tumor cells had to show some degree of staining (+, ++, or +++). AMACR expression was also converted to a yes/no variable.

Table 1. Antibodies and Antigen-retrieval Techniques Applied
AntibodyRetrievalSourceDilution
  1. AMACR indicates α-methylacyl-coenzyme A racemase; PK, pressure cooker; MW, microwave.

AMACR (p504S)ST CC1Zeta Corporation1:100
β-tubulin IPK, 125°C, 3 minChemicon1:1000
β-tubulin IIIPK, 125°C, 3 minChemicon1:2000
Cyclin D1CC1 (Ventana)LabVision1:250
p27CC1 (Ventana)BD Transduct1:5000
p21CC1 (Ventana)BD Transduct1:80
Ki-67 (Mib 1)PK, 121°C, 5 minDAKO1:800
p53MW, 98°C, 60 minDAKO1:200
Bcl-2MW, 98°C, 60 minDAKO1:400
ApopTagPK, 37°C, 15 minChemiconKit

Statistical Analysis

The Wilcoxon signed-rank test was used to study the correlation between the expression of different markers in the pretreatment and posttreatment specimens because of nonparametric and paired values. A Bonferroni adjustment for multiple comparisons was used, with P values <.005 considered significant. The Cox and Kaplan-Meier models were used to determine any possible association between continuous or nominal markers, respectively, and biochemical failure.

The patients who received treatment with neoadjuvant docetaxel also were matched on biopsy GS and preoperative PSA (iPSA) levels 1:1 with untreated patients, and the results were analyzed by using chi-square or Fisher exact texts, as appropriate; Cox proportional-hazards regression; and the Kaplan-Meier method. The level of statistical significance was P < .05, and all P values were 2-sided. Statistical calculations were performed using the StatView software package (version 5.0; SAS Institute Inc., Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Twenty-eight patients completed chemotherapy and underwent RP at the Cleveland Clinic. Pretreatment PBx specimens were reviewed in all patients, and unstained sections of formalin-fixed tissue were available in 11 patients. The median patient age was 62 years (range, 49–72 years), and the median preoperative iPSA level was 6.8 ng/mL (range, 2.5–24 ng/mL). At a median follow-up of 49.5 months (range, 23–72 months), 12 patients (43%) remained clinically and biochemically disease free with no additional therapy, and 16 patients (57%) had biochemical failure. The pretreatment GS was 6 in 2 patients (7%), 7 in 10 patients (36%), 8 in 11 patients (39%), and 9 in 5 patients (18%). Two patients (7.1%) had organ-confined disease, and 23 patients (82.1%) had EPE. Four patients (14.3%) had positive lymph nodes, and 11 patients (39.3%) had seminal vesicles involvement.

Pathologic analyses of the RP specimens demonstrated residual PCa in all patients. Compared with preoperative PBx specimens, most benign prostatic glands showed prominent basal cells and urothelial metaplasia after docetaxel treatment. Corpora amylacea with dense central core were present in all patients. The prostate glands from patients with PCa showed some changes that were attributable to treatment (“treatment effect”). Some degree of cytoplasmic vacuolization and/or clear cell changes was detected in all tumors (Fig. 1). Needle-like, crystalloid structures were noted in the lumen of neoplastic glands in approximately 50% of patients (Fig. 2). Dense intraluminal secretions frequently were present in cancer glands. Cribriform glands with central necrosis were noted in few patients.

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Figure 1. Cytoplasmic vacuolization and clear cell changes in prostate tumors that were treated with neoadjuvant docetaxel chemotherapy. Notice the presence of needle-like, crystalloid structures in the lumen of some of the neoplastic glands.

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Figure 2. High-power view of needle-like, crystalloid structures in the lumen of the prostate glands that were treated with neoadjuvant docetaxel chemotherapy.

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IHC staining analyses for AMACR, β-tubulin I, β-tubulin III, cyclin D1, p27, p21, Ki-67, p53, Bcl-2, and ApopTag were performed on a TMA that contained the posttreatment tissues (RP) and on unstained PBx slides, when available. When we compared the IHC staining pattern between PBx (n = 11 specimens) and corresponding RP specimens using the Wilcoxon signed-rank test, the expression levels of p53 (median, 5% vs 0%; P = .017) (Fig. 3) and Bcl-2 (median, 1% vs 0%; P = .014) (Table 2) after treatment were increased significantly. However, when we performed a Bonferroni adjustment, these differences were no longer significant (P > .005). Increased expression in posttreatment specimens, compared with the expression in pretreatment specimens, was observed for Ki-67 (median, 5% vs 3%; P = .730), ApopTag (median, 0.5% vs 0%; P = .140), β-tubulin I (median, ++ vs +; P = .100), and β-tubulin III (median, + vs 0; P = .080); however, the increase was not significant (Table 2).

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Figure 3. Expression of p53 in a prostate tumor that was treated with neoadjuvant docetaxel chemotherapy.

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Table 2. Pretreatment Versus Posttreatment Marker Expression (Wilcoxon Signed-rank Test; n = 11)
VariablePPretreatment (%)Posttreatment (%)Direction
MedianMeanMedianMean
  • AMACR indicates α-methylacyl-coenzyme A racemase.

  • *

    Staining for AMACR, β-tubulin I, β-tubulin III, and cyclin D1 was scored visually and stratified into 4 groups as follows: − (negative), + (weak), ++ (moderate), and +++ (strong).

Marker
 Ki-76.730310.657.6Up
 p53.01703.258.6Up
 Bcl-2.01400.310.9Up
 p27.7706058.26055.5Equal
 p21.13000.603Equal
 ApopTag.14000.30.53.5Up
Staining intensity*
 AMACR.530++++++++Equal
 Cyclin D.070+++++++Equal
 β-tubulin III.080++Up
 β-tubulin I.100++++++Up

Different degrees of AMACR expression (weak, +; moderate, ++; or strong, +++) was detected in 89% and 82% of the RP and PBx specimens, respectively, with a strong staining pattern (+++) in 46% and 55% of the positive specimens, respectively. Expression of p27 was detected in 96% of RP specimens and 91% of PBx specimens, expression of p21 was detected in 59% of RP specimens and 18% of PBx specimens, and expression of cyclin D1 was detected in 92% of RP specimens and 73% of PBx specimens. Expression levels of AMACR (median, ++ vs ++; P = .530), p27 (median, 60% vs 60%; P = .770), p21 (median, 0% vs 0%; P = .130), and cyclin D1 (median, ++ vs ++; P = .070) were comparable in pretreatment and posttreatment specimens (Table 2). The posttreatment expression levels of the markers that were evaluated in this study were not significantly predictive of biochemical recurrence (Table 3).

Table 3. Posttreatment Markers (n = 28) and Biochemical Failure (Univariate Cox Model)
MarkerMean, %Range, %Wald P
  1. AMACR indicates α-methylacyl-coenzyme A racemase; NA, not available.

AMACR20–3.360
β-tubulin III10–3.670
β-tubulin I21–3.150
Cyclin D120–3.410
p27650–100.970
p2110–20.120
Ki-6750–30.840
p5350–60.170
Bcl-210–3.330
ApopTag10–40.710
 No. of Patients% 
AMACR  .390
 Negative311.1 
 Positive2488.9 
β-tubulin III  .360
 Negative934.6 
 Positive1765.4 
β-tubulin I  NA
 Negative00 
 Positive23100 
Cyclin D1  .820
 Negative27.7 
 Positive2492.3 

The 28 patients who received treatment with neoadjuvant docetaxel (cases) were matched on biopsy GS and preoperative iPSA level 1:1 with untreated patients (controls) from the same institution. The control group was chosen by using random number generator tables and spanned the same years as the case group. The GS and iPSA were pooled and matched (GS: 2–6, 7, and 8–10; iPSA: 0–4 ng/mL, 4–10 ng/mL, 10–20 ng/mL, and >20 ng/mL).

The results were analyzed using Kaplan-Meier analysis (Fig. 4), and chi-square tests, and Fisher exact tests (Table 4). Patients in the control group had a minimum of 24 months of PSA follow-up. The PSA follow-up for patients in the case group ranged from 23 months to 72 months (median, 48.5 months). The time to biochemical failure for cases and controls ranged from 0 months to 71 months (median, 36.5 months). The controls had lower clinical T classification (Fisher exact test; P < .001) and less EPE (chi-square test; P = .002). The difference in biochemical outcome of the 2 groups was not statistically significant (log-rank test; P = .390) (Fig. 4).

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Figure 4. Biochemical recurrence-free survival for cases (circles) and controls (triangles).

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Table 4. Docetaxel Cases and Controls Matched on Pretreatment Diagnostic Prostate Biopsy, Gleason Score, and Initial Prostate-specific Antigen Level
VariableCases (n = 28)Controls (n = 28)P*
No.%No.%
  • EPE indicates extraprostatic extension; SV, seminal vesicles; LN, lymph nodes.

  • *

    Chi-square test.

  • Fisher exact test.

Age, y    .260
 <652071.41657.1 
 ≥65828.61242.9 
Clinical tumor stage
 T1-T2a828.62278.6<.001
 T2b-T2c1553.6414.3 
 T3517.827.1 
Year    .540
 2000725.0621.4 
 20011242.9828.6 
 2002621.4828.6 
 2003310.7621.4 
EPE    .002
 Negative517.91657.1 
 Positive2382.11242.9 
Margins    .760
 Negative21752071.4 
 Positive725828.6 
SV    .250
 Negative1760.72175.0 
 Positive1139.3725.0 
LN    .990
 Negative2485.72589.3 
 Positive414.3310.7 

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

It has been demonstrated that a class of taxanes has significant antitumor activity in men with hormone-refractory PCa when administered either as single agents or in combination with estramustine. The results from 2 randomized studies, Southwest Oncology Group 9916 and TAX 327 (an industry-sponsored, phase III trial), which compared docetaxel-based chemotherapy with mitoxantrone-based therapy, demonstrated a statistically significant survival advantage for a docetaxel-based treatment in patients with castrated, metastatic PCa.2, 3, 6 Given the modest but clinically relevant activity of docetaxel-based therapy in advanced disease, exploration of early administration of systemic therapy is of clinical interest. The increasing capability to predict which patients are likely to have recurrent disease after treatment with RP has led to a growing interest in both neoadjuvant and adjuvant therapies for patients who have a high risk of systemic failure.7

Androgen deprivation therapy administered concomitantly with external beam radiotherapy for selected patients with high-risk disease has demonstrated an improvement in both disease-specific and overall survival.8 In contrast, to date, neoadjuvant hormone therapy prior to RP has not demonstrated any improvement in either the time to clinical progression or survival.9

Recently, neoadjuvant chemotherapy for men with high-risk localized PCa has been tested in several small clinical trials.5, 10–16 For patients who received single-agent docetaxel, a substantial PSA decline (>50%) was observed in 50% to 100% of patients, but no pathologic complete response was reported.5, 11, 15

Similar to the study by Febbo et al., we detected no pathologically complete responses in patients with high-risk, localized PCa who received docetaxel prior to undergoing RP.11 However, there are some histologic changes that are present more commonly in RP specimens than in PBx specimens, including basal cell hyperplasia and urothelial metaplasia in benign glands and clear cell changes and vacuolation in cancer cells. Some of the morphologic changes occurring in PCa glands that are attributable to “treatment effect” may be explained by the inhibition of microtubule disassembly by taxanes. The polymerization of the tubules may be responsible for the cytoplasmic vacuolization and for the needle-like, crystalloid structures noted in the lumen of neoplastic glands.

The mechanisms of cytotoxicity of taxanes/taxoids in PCa undoubtedly are complex. Taxanes are potent inhibitors of microtubule disassembly by promoting polymerization of the tubules and appear to initiate the apoptotic process by binding to β-tubulin and promoting its polymerization.17 Consequently, cells are arrested in the G2/M phase of the cell cycle, after which, they either may undergo cell death by apoptosis or necrosis or they may overcome the G2/M stop and continue in the division cycle. The down-regulation of Bcl-2 and/or the up-regulation of p53 certainly are among the important modes proposed for the induction of apoptosis by taxanes.4

To elucidate the mechanism of action of docetaxel and the tissue effect on PCa, we evaluated the expression of surrogate biomarkers involved in microtubule polymerization and in the proapoptotic and antiapoptotic pathways. In our study, we observed the up-regulation of Bcl-2 (P = .014) and p53 (P = .017) after treatment by using the Wilcoxon signed-rank test. However, when we used a Bonferroni adjustment, these differences were no longer significant (P > .005). The expression levels of β-tubulin I, β-tubulin III, and ApopTag also were increased slightly in posttreatment specimens compared with the corresponding pretreatment specimens, although the difference was not statistically significant.

The up-regulation of p53 and the increased expression of ApopTag detected in the posttreatment specimens support the mechanism proposed for apoptosis induction by taxanes. The increased expression of β-tubulin I and β-tubulin III in the same set of specimens is in keeping with the results from preclinical studies suggesting that docetaxel has a somewhat greater affinity for tubulin than paclitaxel.17

The discordant finding of posttreatment up-regulation of p53 in association with the up-regulation of Bcl-2 and increased expression of Ki-67 in the same set of patients may be explained by the clonal heterogeneity of PCa cells and by the existence of different proapoptotic and antiapoptotic pathways identified in PCa cell lines and tissues. The possibility that the findings described above were the result of chance and small sample size also should be considered.

None of the markers expressed in posttreatment PCa samples were significantly predictive of biochemical recurrence. When patients who were treated with neoadjuvant docetaxel (cases) were matched on biopsy GS and preoperative PSA 1:1 with untreated patients (controls) and the results were analyzed by using Kaplan-Meier and Cox proportional-hazards analyses, the difference in biochemical outcome for the 2 groups was not statistically significant (log-rank P = .390).

Febbo et al. used oligonucleotide microarrays to measure the gene expression in tumors from patients who had received neoadjuvant docetaxel for 6 months and compared it with the gene expression in untreated prostate tumors. Although there were 332 genes with small but significant differences in expression between the 2 groups, there were no genes with large (>5-fold) changes in expression between treated and untreated prostate tumors. A set of genes involved in androgen and estrogen metabolism was identified that was up-regulated in the treated samples. Those authors suggested that the genes identified may account in part for the decline in PSA levels after neoadjuvant docetaxel administration and may be a potential mechanism for chemotherapy resistance.11 The results of both gene expression and IHC analyses suggest that the tissue effect of docetaxel is quite inadequate and certainly argues against using this agent as neoadjuvant monotherapy.

Given the marked clonal heterogeneity of PCa, multimodality approaches directed against multiple molecular targets, rather than single-agent therapy, may be necessary to eradicate adequately the entire malignant cell population. New molecularly targeted agents may interact favorably with taxanes and enhance the apoptotic response or circumvent cellular adaptations that confer drug resistance. An accurate examination of the molecular pathways involved in tumor progression and resistance to treatment and further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors will play a key role in the development of future taxane-based therapies for PCa.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Supported by a grant from Aventis Pharmaceuticals.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES