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In Vitro Cytotoxic Effect of Melphalan and Pilot Phase II Study in Hormone-Refractory Prostate Cancer

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In Vitro Cytotoxic Effect of Melphalan and Pilot Phase II Study in Hormone-Refractory Prostate Cancer ANTICANCER RESEARCH 26: 2197-2204 (2006) In Vitro Cytotoxic Effect of Melphalan and Pilot Phase II Study in Hormone-refractory Prostate Cancer PHILIPPE MOUGENOT1,2, FRANÇOISE BRESSOLLE1,2, STÉPHANE CULINE3, ISABELLE SOLASSOL1, SYLVAIN POUJOL1 and FRÉDERIC PINGUET1 1Onco-pharmacology Department, Pharmacy Service and 3Department of Medicine, Val d’Aurelle Anticancer Centre, parc Euromédecine, Montpellier; 2Clinical Pharmacokinetic Laboratory, University Montpellier I, Montpellier, France Abstract. The objective of this study was to determine the considered the most adequate first-line treatment and impact of single versus sequential exposure to melphalan on controls symptoms in 80-90% of patients (1-3). The median the proliferation of an androgen-independent prostate cell line, duration of response is approximately 2-3 years. PC-3, and to report the results of a pilot phase II study. For Chemotherapy is the next option for hormone-refractory exposure to a single bolus dose, the doses were added at the prostate cancer, but historically chemotherapy treatment start of the study and cell culture was continued for 96 h. For has produced relatively low response rates. sequential exposure, 1/9 of the dose was added every 1.5 h over Alkylating agents may be active against prostate cancer. 12 h, followed by cell culture for 84 h. Cell growth inhibition Single-agent studies of cyclophosphamide (4), nitrogen was determined by the MTT assay. The clinical study was mustard (4), prednimustine (5), estramustine phosphate (6) carried out on 14 patients with advanced prostate cancer. and diazoquinone (7) have reported response rates of 10 to Melphalan was infused over a 24-h period. The sequential-dose 20%. Smith et al. (8) estimated the single-agent activity of schedule was more effective than the single-dose exposure, IC50 intravenous (over 30 min) melphalan in 27 hormone- values: 0.074 versus 0.77 Ìg/ml. Out of the 14 patients (42 resistant prostate cancer patients. No objective responses to courses) enrolled into the study, two patients were removed this regimen were observed by the authors; the median within the first 2 weeks because of rapid disease progression. survival was 11.5 months. However, a decrease of >50% in The toxicity profile did not differ greatly from that reported serum prostate-specific antigen (PSA) levels, that was after a 1-h infusion. Four PR and two SD were observed. The sustained for >6 weeks, was observed in two patients and median survival of the twelve patients was 23 weeks. one patient survived for more than 29 months. More Melphalan administered over a 24-h period to patients with recently, chemotherapies with estramustine and the androgen-independent prostate cancer appeared to provide mitoxantrone/prednisone combination, approved by the some clinical benefits with manageable toxicity. Food and Drug Administration for use in this indication, have produced more promising palliative activity (9-11). Prostate cancer is the most common malignancy diagnosed Nevertheless, no treatment has been shown to prolong in men. However, the management of metastatic prostate survival. The drug resistance of prostate carcinoma would cancer remains a complex and difficult problem as there are be due to high levels of TNF-beta that protect tumors from limited treatment options and the prognosis continues to be cytotoxic cancer therapies (12). dismal in metastatic hormone-refractory prostate cancer. In Melphalan is an alkylating agent of the bischloroethylamine newly diagnosed metastatic disease, the suppression of type. It exerts a cytotoxic effect through the formation of androgenic activity, with or without anti-androgens, is inter-strand or intra-strand DNA cross-links or DNA-protein cross-links via the two chloroethyl groups of the molecule (13). Founded on the pharmacokinetic principles of phase- specific, plasma half-life and stability in solution, infusional Correspondence to: Dr. Françoise Bressolle, Ph.D., Laboratoire de schedules for chemotherapy administration represent a Pharmacocinétique Clinique, Faculté de Pharmacie, BP 14491, rational method for the delivery of many antineoplastic 34093 Montpellier Cedex 5, France. Tel: (33) 4 67 54 80 75, Fax: (33) 4 67 54 80 75, e-mail: [email protected] agents. For several antimitotic drugs, long-term continuous infusion increases the therapeutic activity or improves the Key Words: Melphalan, 24-hour continuous infusion, PC-3 cell line, therapeutic index by decreasing toxicity (14). Based on hormone-refractory prostate cancer, survival. pharmacokinetic considerations, melphalan is also a good 0250-7005/2006 $2.00+.40 2197 ANTICANCER RESEARCH 26: 2197-2204 (2006) candidate for continuous infusion; indeed, this drug has a centrifugation and washing with PBS IX, a nuclear suspension in short half-life, a small volume of distribution and a low protein PBS was obtained at a density of 200,000 cells/ml. DNA binding binding (15). However, due to its low stability in 5% dextrose was then performed with propidium iodide. The samples were analyzed using the EPIC XL Flow Cytometer (Coulter, Hialeah, and 0.9% sodium chloride, melphalan is usually administered FL, USA). Histogram analyses of the DNA distribution were by short-term infusion. However, a previous study showed that carried out using the «Multicycle» software (Coulter), which the stability of melphalan can be increased using 3% sodium allowed an accurate estimation of the S-phase. The coefficient of chloride (16). Consequently, it would be possible to consider variation was <2%. administering melphalan by continuous infusion. In a previous To evaluate the apoptotic capacity of the cell populations, in vitro study carried out on two human cell lines, one immunocytology (IC) was performed using the Bcl-2 anti-apoptotic myeloma and one ovary carcinoma (8226 and A2780, antibody (Bcl-2 oncoprotein, clone 124, Dakocytomation S.A., Trappes, France). For this, cells were prepared as described above. respectively), the antitumor activity of melphalan was higher Cytospin slides were obtained from 200 Ìl of the solution, fixed for sequential- than single-dose exposure (17). Based on with a methanol-acetone (50:50, v/v) fixative mixture at –20ÆC for results of a phase I trial, the maximum tolerated dose of 10 min and IC was carried out using the LSABR 2 peroxidase kit melphalan infused over a 24-h period was 30 mg/m2 (18). (Dakocytomationn S.A.). Simultaneously, both the hormonal The first objective of the present study was to determine receptor status of the cell lines, using an estrogen receptor the impact of single versus sequential exposure to melphalan antibody (clone 6F11, Dako, Glostrup, DK) and a progesterone on the proliferation of an androgen-independent prostate receptor antibody (PSR636, Dako), as well as the level of expression of the cerbB2-neu protein, using the CB11 monoclonal cell line, PC-3. The second objective was to report the antibody (Dako), were studied by IC. results of a phase II pilot study initiated to determine the To analyze DNA damage in the cell populations, the alkaline efficacy and toxicity of melphalan, administered over a 24-h Comet assay, a single-cell gel electrophoresis, was employed, period with an adapted individual dosing, in advanced according to a previously published method (19). Slide analysis was prostate cancer. done on a fluorescent microscope (Leica) with a cold triCCD camera, using SAMBA IPS Software, which enabled the “tail Patients and Methods moment” (TM) of a 50-cell comet to be determined. Drug and chemicals. Melphalan (L-PAM) was kindly provided by Cell growth inhibition and viability. On day 0, the RPMI medium Glaxo-SmithKline (Paris, France). 3-(4,5-dimethylthiazol-2-yl)-2.5- was carefully removed from the flasks and the cells, in exponential- diphenyltetrazolium bromide (MTT) and phosphate-buffered phase growth, were harvested with 3 ml of trypsin-EDTA 1N saline pH 7.3 (PBS) were purchased from Sigma Chemical Co. (St. (Gibco Laboratories, Cergy Pontoise, France) for 5 min at 37ÆC, Louis, MO, USA). RPMI medium containing RPMI-1640, heat- were washed with 5 ml of RPMI medium and then centrifuged. inactived (56ÆC) fetal calf serum (FCS) and L-glutamine were The supernatant was removed and the pellet was resuspended in obtained from Gibco-BRL (Cergy-Pontoise, France). Isopropyl RPMI medium. The cells were counted then diluted in complete 3 alcohol and hydrochloric acid were of analytical grade (both from culture medium to a final density of 50x10 cells/ml. One hundred Merck, Darmstadt, Germany). Ìl of cell suspension (i.e., 5000 cells/well) were dispensed with a The complete culture medium consisted of RPMI medium pipette into each individual well of a lidded 96-well tissue culture supplemented with 10% FCS, 2 mM L-glutamine, 100 IU/ml plate (TPP, Trasadingen, Switzerland). The cells were re-incubated penicillin G sodium, 100 Ìg/ml streptomycin sulphate and 0.25 Ìg/ml at 37ÆC in a humidified atmosphere (about 17 h) to allow for amphotericin B. attachment. Melphalan was reconstituted in a water/ethanol/propylene-glycol Cell line and culture techniques. The experiments were conducted mixture (35:5:60, v/v), diluted in complete culture medium and with a human androgen-insensitive prostatic carcinoma cell line, added to the wells. For single-dose exposure, the doses of PC-3, obtained from the American Type Culture Collection melphalan were added only at the start of the study and the cell (Rockville, MD, USA). This cell line was cultured at 37ÆC, in flasks culture was continued for 96 h (i.e., 4-fold the doubling-time). For containing complete culture medium, under 95% relative humidity sequential exposure, 1/9 of the total dose was added at the in an atmosphere containing 5% carbon dioxide in air and was beginning of the study and every 1.5 h during the subsequent 12 h, routinely passaged when 90-95% confluent. Only exponentially- followed by cell culture for 84 h. The total dose in the two arms of growing viable cells were used for the study.
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