Exercise and the Tumor Microenvironment: Potential Therapeutic Implications.

An imbalance in oxygen delivery to demand in solid tumors results in local areas of hypoxia leading to poor prognosis for the patient. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously nonperfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers.

Effects of aging and exercise training on the dynamics of vasoconstriction in skeletal muscle resistance vessels.

It is unknown whether aging or exercise training affect the dynamics of arteriolar vasoconstriction. PURPOSE: We hypothesized that old age will slow, and exercise training will speed, the dynamics of skeletal muscle arteriolar vasoconstriction in resistance vessels of aged rats. METHOD: Young (6 month old) and aged (24 month old) male Fischer-344 rats were assigned to sedentary (Sed: n = 6/age group) or exercise-trained (ET: n = 5 aged and 6 young; via treadmill running for 10-12 weeks) groups. After completion of training, arterioles from the red portion of the gastrocnemius muscle were removed, cannulated, and exposed to 10-4 M norepinephrine (NE) or 20 mM caffeine. Changes in luminal diameter were recorded for analysis of constrictor dynamics. RESULT: Old age blunted all kinetic parameters (i.e., time delay, time constant) resulting in vasoconstriction taking ~3 times as long to reach a steady state (SS) versus younger counterparts for NE (aged-sed: 15.6 ± 6.0 versus young-sed: 4.6 ± 0.5 s; P < 0.05) with a similar time course to caffeine. Exercise training resulted in a similar time to SS between age groups for NE (aged-ET: 6.8 ± 1.6 versus young-ET: 7.0 ± 0.6 s) and caffeine (aged-ET: 7.8 ± 0.6 versus young-ET: 8.6 ± 1.0 s). CONCLUSION: The results of this study demonstrate that aging blunts the rate of vasoconstriction in skeletal muscle resistance vessels to the sympathetic neurotransmitter NE due, in part, to an attenuated rate of contraction from intracellular calcium release. Further, exercise training speeds the dynamics of constriction to both NE and caffeine with old age.

Head-up tilt does not enhance prostate tumor perfusion or oxygenation in young rats.

Solid tumors contain hypoxic regions that contribute to anticancer therapy resistance. Thus, mitigating tumor hypoxia may enhance the efficacy of radiation therapy which is commonly utilized for patients with prostate cancer. Increasing perfusion pressure in the prostate with head-up tilt (HUT) may augment prostate tumor perfusion and decrease hypoxia. The purpose of this study was to determine if an increase in the vascular hydrostatic gradient via 70° HUT increases tumor perfusion and decreases tumor hypoxia in a preclinical orthotopic model of prostate cancer. Male Copenhagen rats (n = 17) were orthotopically injected with Dunning R-3327 (AT-1) prostate adenocarcinoma cells to induce prostate tumors. After tumors were established, prostate tumor perfusion and hypoxia were measured in rats during level (0°) and 70° HUT positions. To compare the magnitude of the hydrostatic column to that present in humans, ultrasound was used to measure the heart to prostate distance in male human subjects to estimate the prostate vascular hydrostatic pressure with the upright posture. In young rats, no differences were detected in prostate tumor perfusion or prostate tumor hypoxia with 70° HUT versus the level position. However, from the retrospective study, young rats increased prostate vascular resistance to HUT, whereas aged rats lacked this response. Tumor vessels co-opted from existing functional vasculature in young rats may be sufficient to negate increases in perfusion pressure with HUT seen in aged rats. Additionally, in humans, the estimated hydrostatic column at the level of the prostate is five times greater than that of the rat. Therefore, 70° HUT may elicit increases in prostate/prostate tumor blood flow in humans that is not seen in rats.

Effects of high-intensity training on prostate cancer-induced cardiac atrophy.

BACKGROUND: Recent evidence suggests prostate cancer independent of treatment has atrophic effects on whole heart and left ventricular (LV) masses, associated with reduced endurance exercise capacity. In a pre-clinical model, we tested the hypothesis that high-intensity training could prevent cardiac atrophy with prostate cancer and alter cardiac protein degradation mechanisms. METHODS: Dunning R-3327 AT-1 prostate cancer cells (1×105) were injected into the ventral prostate lobe of 5-6 mo immunocompetent Copenhagen rats (n=24). These animals were randomized into two groups, tumor-bearing exercise (TBEX, n=15) or tumor bearing sedentary (TBS, n=9). Five days after surgery, TBEX animals began exercise on a treadmill (25 m/min, 15° incline) for 45-60 min/day for 18±2 days. Pre-surgery (Pre), and post-exercise training (Post) echocardiographic evaluation (Vivid S6, GE Health Care), using the parasternal short axis view, was used to examine ventricle dimensions. Markers of protein degradation (muscle atrophy F-box, Cathepsin B, Cathepsin L) in the left ventricle were semi-quantified via Western Blot. RESULTS: There were no significant differences in tumor mass between groups (TBEX 3.4±0.7, TBS 2.8±0.6 g, P=0.3), or body mass (TBEX 317±5, TBS 333±7 g, P=0.2). Heart-to-body mass ratio was lower in TBS group compared to TBEX (2.3±0.1 vs. 2.5±0.1 mg/g, P<0.05). LV/body mass ratio was also lower in the TBS group (1.6±0.1 vs. 1.8±0.1 mg/g, P<0.05). From Pre-Post, TBEX had significant increases in SV (~20% P<0.05) whereas TBS had no significant change. There were no significant differences between groups for markers of protein degradation. CONCLUSION: This study suggests that high-intensity exercise can improve LV function and increase LV mass concurrent with prostate cancer development, versus sedentary counterparts. Given cardiac dysfunction often manifests with conventional anti-cancer treatments, a short-term high-intensity training program, prior to treatment, may improve cardiac function and fatigue resistance in cancer patients.

Effects of prostate cancer and exercise training on left ventricular function and cardiac and skeletal muscle mass.

Prostate cancer was found to reduce cardiac and left ventricle (LV) masses in association with diminished exercise capacity in rats. We tested the hypothesis that exercise training will mitigate prostate cancer-induced cardiac and skeletal muscle atrophy and improve LV function versus sedentary tumor-bearing counterparts. Copenhagen rats ( n = 39; ~5 mo old) were randomized into four groups: exercise-trained tumor-bearing (EXTB) or control (EXCON) and sedentary tumor-bearing (SEDTB) or control (SEDCON). Dunning R-3327 prostate cancer cells were injected orthotopically in 19 of the 39 animals. Treadmill exercise training was performed for 60 min/day for ~30 days. Animals underwent echocardiography to examine ventricle dimensions "Pre-" cancer injection or exercise (PRE) and 15 (Post 1) and 32-35 (Post 2) days after cancer cell injection with tissues collected after Post 2. LV TNF-α and IL-6 concentrations were measured post mortem. Cardiac and LV mass of SEDTB animals were lower than all groups ( P < 0.05). Tumor mass was negatively correlated with LV mass in EXTB (-0.75, P < 0.02) and SEDTB animals (-0.72, P < 0.02). EXCON group had higher stroke volume Post 2 assessment compared with both sedentary groups ( P < 0.05) but not EXTB animals. No difference in LV [IL-6] or [TNF-α] was found between the cancer groups. The current investigation demonstrates prostate cancer, independent of anticancer treatment, significantly reduces cardiac mass and LV mass as well as locomotor muscle masses. However, moderate-intensity exercise training can mitigate cardiac and skeletal muscle atrophy with prostate cancer and preserve the cardiac phenotype (i.e., mass and function) to that of the healthy sedentary group. NEW & NOTEWORTHY This study demonstrates the atrophic effects of prostate cancer on cardiac and skeletal muscle mass independent of anticancer treatment(s) that can be mitigated with moderate-intensity exercise. These findings have important implications for potentially improving the quality of life as well as therapeutic outcomes for patients with prostate cancer.

Prostate cancer cell growth characteristics in serum and prostate-conditioned media from moderate-intensity exercise-trained healthy and tumor-bearing rats.

Physical activity is associated with diminished risk of several cancers, and preclinical studies suggest exercise training may alter tumor cell growth in certain tissue(s) (e.g., adipose). From moderate-intensity exercise-trained rats versus sedentary controls, we hypothesized 1) there will be a decreased prostate cancer cell viability and migration in vitro and, within the prostate, a reduced 5α-reductase 2 (5αR2) and increased caspase-3 expression, and 2) that exercise training in tumor-bearing (TB) animals will demonstrate a reduced tumor cell viability in prostate-conditioned media. Serum and prostate were harvested from sedentary or exercise-trained (treadmill running, 10-11 weeks) immune-competent (Copenhagen; n = 20) and -deficient (Nude; n = 18) rats. AT-1 and PC-3 prostate cancer cells were grown in one or more of the following: serum-supplemented media (SSM), SSM from TB rats (SSM-TB), prostate-conditioned media (PCM) or PCM from TB rats (PCM-TB) for 24-96 h under normoxic (18.6% O2) or hypoxic (5% O2) conditions. Under normoxic condition, there was a decreased AT-1 cell viability in SSM and PCM from the exercise-trained (ET) immune-competent rats, but no difference in PC-3 cell viability in SSM and PCM from ET Nude rats versus the sedentary (SED) group, or in SSM-TB from ET-TB Nude rats versus the SED-TB group. However, there was a decreased PC-3 cell viability in the PCM-TB of the ET-TB group versus SED-TB group. PC-3 cell viability in all conditioned media types was not altered between groups with hypoxia. In the prostate, exercise training did not alter 5αR2 expression levels, but increased caspase-3 expression levels. In conclusion, prior exercise status reduced prostate cancer cell viability in the serum and prostate of trained rats but did not modify several other key prostate tumor cell growth characteristics (e.g., migration, cell cycle except in S phase of PC-3 cells in PCM-TB). Importantly, once the tumor was established, exercise training reduced tumor cell viability in the surrounding prostate, which may help explain the reduced severity of the disease in patients that exercise.

Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation.

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4-8 mo, n = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; P ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; P ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; P ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression (P ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; P ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms.NEW & NOTEWORTHY Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.

The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates.

BACKGROUND: Previously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective. METHOD/PRINCIPAL FINDINGS: Ki-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development. CONCLUSION: The effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores.

BACKGROUND: The contribution of 5α-reductase 1 and 5α-reductase 2 to prostate cancer development and progression is not clearly understood. TRAMP mice are a common prostate cancer model, in which 5α-reductase 1 and 5α-reductase 2 expression levels, along with prostate lesions scores, have not been investigated at different time points to further understand prostate carcinogenesis. METHOD/PRINCIPAL FINDINGS: To this end, 8-, 12-, 16-, and 20-week-old male C57BL/6TRAMP x FVB mice prostate most severe and most common lesion scores, 5α-reductase 1 and 5α-reductase 2 in situ hybridization expression, and Ki-67, androgen receptor, and apoptosis immunohistochemistry levels were measured. Levels of these markers were quantified in prostate epithelium, hyperplasia, and tumors sections. Mice developed low- to high-grade prostatic intraepithelial neoplasia at 8 weeks as the most severe and most common lesions, and moderate- and high-grade prostatic intraepithelial neoplasia at 12 and 16 weeks as the most severe lesion in all lobes. Moderately differentiated adenocarcinoma was observed at 20 weeks in all lobes. Poorly differentiated carcinoma was not observed in any lobe until 12-weeks-old. 5α-reductase 1 and 5α-reductase 2 were not significantly decreased in tumors compared to prostate epithelium and hyperplasia in all groups, while proliferation, apoptosis, and androgen receptor were either notably or significantly decreased in tumors compared with prostate epithelium and hyperplasia in most or all groups. Prostate 5αR1 levels were positively correlated with adjusted prostate most severe lesion scores. CONCLUSION: Downregulation of androgen receptor and 5α-reductase 2, along with upregulation of 5α-reductase 1 in tumors may promote prostatic intraepithelial neoplasia and prostate cancer development in TRAMP mice.

Prostate cancer reduces endurance exercise capacity in association with reductions in cardiac and skeletal muscle mass in the rat.

Exercise capacity is reduced in prostate cancer patients concurrently treated with androgen deprivation therapy compared to healthy counterparts. We tested the hypothesis that prostate cancer independently reduces endurance exercise capacity in a preclinical orthotopic prostate tumor model. Male Copenhagen rats performed an initial treadmill running test to exhaustion. The rats' prostates were subsequently injected with either prostate tumor cells (R-3327 AT-1, tumor bearing, n=9) or vehicle control (sham, n=9) and the treadmill tests were repeated four and eight weeks post-surgery. Left ventricle contractility (LV Δpressure/Δtime) was subsequently measured under anesthesia and the heart and select hindlimb muscles were dissected and weighed. Initial times to exhaustion were not different between groups (sham: 28.24±1.26, tumor bearing: 28.63±2.49 min, P=0.90). Time to exhaustion eight weeks post-surgery was reduced compared to initial values for both groups but was significantly lower in the tumor bearing (13.25±1.44 min) versus the sham (21.17±1.87 min, P<0.01) group. Within the tumor bearing group, LV Δpressure/Δtime was significantly negatively correlated with tumor mass (-0.71, P<0.05). Body mass at eight weeks post-surgery was not different between groups (P=0.26) but LV mass (↓17%, P<0.01), as well as the mass of select hindlimb skeletal muscles, was significantly lower in the tumor bearing versus sham group. Within the tumor bearing group, LV muscle mass was significantly negatively correlated with prostate tumor mass (r=-0.85, P<0.01). Prostate cancer reduced endurance exercise capacity in the rat and reductions in cardiac function and mass and skeletal muscle mass may have played an important role in this impairment.

Newly formulated, protein quality-enhanced, extruded sorghum-, cowpea-, corn-, soya-, sugar- and oil-containing fortified-blended foods lead to adequate vitamin A and iron outcomes and improved growth compared with non-extruded CSB+ in rats.

Corn and soyabean micronutrient-fortified-blended foods (FBF) are commonly used for food aid. Sorghum and cowpeas have been suggested as alternative commodities because they are drought tolerant, can be grown in many localities, and are not genetically modified. Change in formulation of blends may improve protein quality, vitamin A and Fe availability of FBF. The primary objective of this study was to compare protein efficiency, Fe and vitamin A availability of newly formulated extruded sorghum-, cowpea-, soya- and corn-based FBF, along with a current, non-extruded United States Agency for International Development (USAID) corn and soya blend FBF (CSB+). A second objective was to compare protein efficiency of whey protein concentrate (WPC) and soya protein isolate (SPI) containing FBF to determine whether WPC inclusion improved outcomes. Eight groups of growing rats (n 10) consumed two white and one red sorghum-cowpea (WSC1 + WPC, WSC2 + WPC, RSC + WPC), white sorghum-soya (WSS + WPC) and corn-soya (CSB14 + WPC) extruded WPC-containing FBF, an extruded white sorghum-cowpea with SPI (WSC1 + SPI), non-extruded CSB+, and American Institute of Nutrition (AIN)-93G, a weanling rat diet, for 4 weeks. There were no significant differences in protein efficiency, Fe or vitamin A outcomes between WPC FBF groups. The CSB+ group consumed significantly less food, gained significantly less weight, and had significantly lower energy efficiency, protein efficiency and length, compared with all other groups. Compared with WSC1 + WPC, the WSC1 + SPI FBF group had significantly lower energy efficiency, protein efficiency and weight gain. These results suggest that a variety of commodities can be used in the formulation of FBF, and that newly formulated extruded FBF are of better nutritional quality than non-extruded CSB+.

Effect of Saw Palmetto Supplements on Androgen-Sensitive LNCaP Human Prostate Cancer Cell Number and Syrian Hamster Flank Organ Growth.

Saw palmetto supplements (SPS) are commonly consumed by men with prostate cancer. We investigated whether SPS fatty acids and phytosterols concentrations determine their growth-inhibitory action in androgen-sensitive LNCaP cells and hamster flank organs. High long-chain fatty acids-low phytosterols (HLLP) SPS ≥ 750 nM with testosterone significantly increased and ≥500 nM with dihydrotestosterone significantly decreased LNCaP cell number. High long-chain fatty acids-high phytosterols (HLHP) SPS ≥ 500 nM with dihydrotestosterone and high medium-chain fatty acids-low phytosterols (HMLP) SPS ≥ 750 nM or with androgens significantly decreased LNCaP cell number (n = 3; p < 0.05). Five- to six-week-old, castrated male Syrian hamsters were randomized to control (n = 4), HLLP, HLHP, and HMLP SPS (n = 6) groups. Testosterone or dihydrotestosterone was applied topically daily for 21 days to the right flank organ; the left flank organ was treated with ethanol and served as the control. Thirty minutes later, SPS or ethanol was applied to each flank organ in treatment and control groups, respectively. SPS treatments caused a notable but nonsignificant reduction in the difference between left and right flank organ growth in testosterone-treated SPS groups compared to the control. The same level of inhibition was not seen in dihydrotestosterone-treated SPS groups (p < 0.05). Results may suggest that SPS inhibit 5α-reductase thereby preventing hamster flank organ growth.

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes.

Preventive and therapeutic efficacy of finasteride and dutasteride in TRAMP mice.

BACKGROUND: The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2. METHOD/PRINCIPAL FINDINGS: Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30-33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma. CONCLUSION: Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.

The effect of finasteride and dutasteride on the growth of WPE1-NA22 prostate cancer xenografts in nude mice.

BACKGROUND: 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen dihydrotestosterone. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5αR1 and decreased 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5αR1 and 5αR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation. METHODOLOGY/PRINCIPAL FINDINGS: Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1-2 weeks prior to or 3 weeks after subcutaneous injection of 1×105 WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive. CONCLUSION: The lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth.