Changes in body composition during androgen deprivation therapy for prostate cancer

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.     

Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.Advances in genomics and cell biology have highlighted the heterogeneity and complexity of cancer. It is generally accepted that cancer is usually the result of a combination of interconnected disease pathways that may not be treated effectively with 1D therapeutic mechanisms (1). The inhibition of a pathway by a single-drug therapy often results in the emergence of drug resistance and tumor relapse, largely because of pathway redundancy, cross-talk, compensatory and neutralizing actions, and antitarget activities that commonly occur with single-drug cancer therapy (2). In some cases, relapse can result in the emergence of phenotypically distinct and possibly more virulent tumors. For example, treatment of prostatic adenocarcinoma with androgen ablation therapies, such as abiraterone or enzalutamide, results in the development of abiraterone or enzalutamide refractory castration-resistant prostate cancer that is phenotypically nonadenocarcinoma and represents a rare and often lethal form of prostate cancer with a neuroendocrine phenotype (3).Platinum agents are among the most widely used cytotoxic agents for cancer therapy. Cisplatin and other DNA adduct-forming chemotherapeutics cause DNA damage as their primary mechanism of cellular cytotoxicity. However, several cellular pathways are activated in response to their interaction with DNA, which include DNA repair pathways that remove the damage and translesion DNA synthesis (TLS) by specialized DNA polymerases that helps the cells tolerate the DNA damage (4, 5). The Rev1/Rev3L/Rev7-dependent error-prone TLS pathway has been shown to play an important role in cisplatin-induced mutations that improve the capacity of tumor cells to either repair or tolerate DNA damage, resulting in acquired chemoresistance (6). Rev1 is a translesion DNA polymerase, while Rev3 is the catalytic subunit of the translesion DNA polymerase Polζ (Rev3L/Rev7). Recent studies using mouse lymphoma and lung cancer models have shown that the suppression of error-prone TLS activity in mammalian cells by knocking down Rev1 or Rev3L can inhibit drug-induced mutagenesis so that relapsed tumors remain sensitive to subsequent treatment (6, 7). It has been suggested that combining conventional chemotherapy with newly emerging siRNA therapeutics could be a promising strategy for improving the efficacy of chemotherapy through additive or synergistic effects (8).Since the discovery of RNAi, synthetic siRNA has emerged as a class of attractive therapeutics for treatment of various diseases, including cancer (9, 10). Given the ability to target and silence nearly any gene of interest, specific siRNA can be constructed to target genes encoding proteins involved in DNA repair and the acquisition of multidrug resistance (6, 11). Naked siRNA cannot readily cross cellular membranes due to its polyanionic and macromolecular characteristics, and it is susceptible to degradation by endogenous enzymes (12). Therefore, considerable efforts have been made to develop safe and effective vehicles to facilitate the delivery of siRNA into cells (13–15). Similarly, the methods by which chemotherapeutics are delivered also have a significant effect on the efficacy (16, 17). Recent research has begun to explore the feasibility of combining chemotherapeutics with siRNA using a variety of nanocarrier platforms (18, 19). One of the earliest efforts using this therapeutic paradigm involved cancer treatment by targeted minicells containing specific siRNA followed by drug-loaded minicells, which efficiently reversed drug resistance in drug-resistant tumors and produced enhanced therapeutic efficacy in inhibiting tumor growth (20). However, to exert optimal synergistic effects, both the drug and siRNA may need to be temporally colocalized in the tumor cells. As a result, nanocarrier platforms that are capable of simultaneously delivering siRNA and anticancer drugs to the same tumor cells are emerging as a promising nanomedicine approach for improved cancer therapy (21, 22).Nanoparticles (NPs) self-assembled from biodegradable PLGA-PEG block copolymers represent a promising class of potential delivery vehicles due to several unique properties: PLGA-PEG copolymers (i) are biocompatible and biodegradable and used in many U.S. Food and Drug Administration-approved products, (ii) are capable of encapsulating small- and macromolecular payloads with a wide range of physiochemical properties, and (iii) can be designed for controlled release through a combination of polymer degradation and drug diffusion (23). Recently, a docetaxel-containing formulation termed BIND-014 (BIND Biosciences), which has been selected from an NP library composed of poly(d,l-lactide), PLGA, and PEG, is currently in phase I clinical trials (24). Another NP system based on PLGA-PEG has been developed by Kolishetti et al. (25) for codelivery of cisplatin and docetaxel, two drugs with different characteristics and metabolic targets, to prostate cancer cells. However, there remains a pressing need to engineer nanocarriers that are capable of delivering combination therapeutics involving siRNA because systemic delivery of siRNA still remains challenging. Herein, we describe an integrated nanodelivery system capable of simultaneously delivering cisplatin prodrug and siRNAs against REV1 and REV3L to enhance chemosensitivity of tumors. PLGA-PEG was formulated with a cationic lipid-like molecule designated as G0-C14 into NPs that comprise three components: an aqueous inner core, a cationic and hydrophobic layer composed of PLGA and G0-C14, and a hydrophilic PEG corona (Fig. 1A). The G0-C14 compound is synthesized with cationic head groups that can efficiently bind siRNA via electrostatic interactions and flexible hydrophobic tails for self-assembly with PLGA-PEG to form Pt(IV)-prodrug encapsulating NPs (Fig. 1A). In this study, we applied a Pt(IV)-prodrug approach previously used in our laboratory to deliver cisplatin (26). In this approach, a unique Pt(IV) precursor compound, c,c,t [Pt(NH₃)₂Cl₂(O₂C(CH₂)₈CH₃)₂] (compound 1; Fig. 1B), was developed to allow the release of cisplatin at a lethal dose upon intracellular reduction. The linear decanoyl chains in compound 1 also enable efficient encapsulation within the hydrophobic layer of NPs and controlled release without compromising either feature (26). We investigated the ability of these polymer/lipid hybrid NPs to down-regulate the expression of target genes as well as to induce diminished resistance and enhanced therapeutic profile both in vitro and in vivo. Using a human Lymph Node Carcinoma of the Prostate (LNCaP) xenograft mouse model of prostate cancer, we further demonstrated that these hybrid NPs containing Pt(IV)-prodrug and REV1/REV3L-specific siRNAs (siREV1, siREV3L) cooperatively suppress tumor growth through synergistic effects.Open in a separate windowFig. 1.(A) Chemical structure of PLGA-PEG/G0-C14 NPs. The particle consists of three components: (i) an outer PEG surface, (ii) a PLGA/G0-C14 layer that plays two roles: (a) acting as a polymer matrix loaded with nonpolar drugs and (b) protecting and promoting siRNA molecule retention inside the NP core and controlling drug release, and (iii) an aqueous inner core containing siRNA. (B) Chemical structure of the hydrophobic platinum(IV) compound 1 and the chemistry by which the active drug cisplatin is released after reduction in the cell. (C) Synthesis of G0-C14 through ring opening of 1,2-epoxytetradecane by ethylenediamine core-PAMAM generation 0 dendrimer. (D) Size distribution of the NPs containing both compound 1 and siRNA determined by dynamic light scattering. (E) Representative transmission EM image of the NPs. (Scale bar, 200 nm.)     

Polymorphism in endostatin,an angiogenesis inhibitor,and prostate cancer risk and survival: A prospective study

Endostatin inhibits endothelial cell proliferation and migration, prerequisites of angiogenesis. A functional missense mutation (D104N) in endostatin was associated with an increased prostate cancer risk in a small study. We undertook a larger, prospective study within the Physicians' Health Study to examine D104N and prostate cancer risk and progression among 544 incident prostate cancer cases (1982–1995) and 678 matched controls. The association between endostatin genotype and cancer risk was estimated using logistic regression models. Among cases, Cox models were used to assess D104N and lethal prostate cancer. Given the role of endostatin in neovascularization of adipose tissue, we cross classified individuals on D104N genotype and body mass index (BMI). The genotype frequency was 1.3% homozygous (NN), 14.5% heterozygous (DN) and 84.2% wildtype homozygous (DD). There was no overall association between carriage of the N allele and prostate cancer risk (RR = 1.2, 95% CI: 0.9–1.6) or cancer‐specific mortality (HR = 1.2, 0.7–1.8). Cases with the polymorphic allele were less likely to be overweight (BMI 25 kg/m² or greater, 26%) compared to men wildtype homozygous (48%), p < 0.0001. Being overweight was associated with a 60% greater prostate cancer risk among those who were wildtype homozygous. In contrast, being overweight was associated with a 50% lower risk of cancer among those with the N allele. We did not confirm an earlier observation between the D104N polymorphism and prostate cancer. However, our data indicate that prostate cancer cases who carry the variant N allele are more likely to be overweight, and may be more susceptible to the angiogenic influences of obesity in prostate cancer pathogenesis. © 2009 UICC     

Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer

The review summarizes the outcomes of several landmark trials involving aromatase inhibitors that helped formulate current therapeutic approaches recommended by the American Society of Clinical Oncology for breast carcinoma treatment.     

Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile

We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.     

Tight binding inhibitors—IX: Kinetic parameters of dihydrofolate reductase inhibited by methotrexate,an example of equilibrium study

Equilibrium studies in the presence of methotrexate (MTX), based on the new theories of tight-binding inhibitors and on classical initial velocity analysis, indicated that the reaction mechanism of dihydrofolate reductase Lactobacillus casei MTX/R is consistent with a rapid equilibrium random bi-bi and that MTX inhibits the enzyme competitively with respect to dihydrofolate but noncompetitively with respect to NADPH. The kinetic parameters determined at pH 7.3 and 23° were: K_m for DHF, 9.8 ± 1.3 μM; K_m for NADPH, 6.0 ± 1.2 μM; K_d for E·DHF, 5.7 ± 0.7 μM; K_d for E·NADPH, 0.037 ± 0.028 μM; K_d for E·MTX, 1.20 ± 0.15 nM; K_d for E·NADPH·MTX → E·NADPH + MTX, 0.19 ± 0.04 nM; and K_d for E·NADPH·MTX → E·MTX + NADPH, 7.6 ± 5.9 nM; the molar equivalency factor was 3.33 ± 0.44 nM per unit/liter of the enzyme, and the catalytic number was 300 min^?.     

Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer

BACKGROUND: Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS: In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS: In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS: Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.