Effect of Xymedon and Mexidol in Combination with Antineoplastic Drugs on Spermatogenesis Indicators and Functional State of Spermatozoa in Rats with Walker-256 Carcinoma.

We compared the effect of Xymedon (100 mg/kg), Mexidol (50 mg/kg), and their combination on spermatogenesis indicators and functional state of spermatozoa in rats with Walker-256 carcinoma treated with doxorubicin (4 mg/kg) and cyclophosphamide (45 mg/kg) (once intraperitoneally on day 11 after tumor cells transplantation). Xymedon and Mexidol were injected intramuscularly for 10 days starting from day 11 of the experiment. The studied parameters were evaluated on experimental days 14 and 21. We have established that gonadoprotective effect of Xymedon developed gradually and persisted longer than that of Mexidol. It manifested in an increase in the number of epithelial spermatogenesis cells (spermatogonia by 3.2 times, early spermatids by 2.2 times, late spermatids by 2.9 times, and Leydig cells by 4 times) in the testes and also the proportion of viable progressively and non-progressively motile epididymal spermatozoa (by 2 times). The combination of Xymedon and Mexidol stimulated spermatogenesis (with restoration of the initial level of spermatocytes, an increase in the number of early spermatids by 65.5 and 99% in comparison with Xymedon alone and Mexidol alone, respectively) and increased the number of viable epididymal spermatozoa more effectively than Xymedon and Mexidol alone by 54 and 60%, respectively.

Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats.

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 107 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.

Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats.

Tumor metastasis to bone can subsequently lead to bone cancer pain (BCP). Currently, BCP is difficult to conquer due to a poor understanding of the potential mechanisms. Several studies have indicated that astrocyte-specific connexin 43 (Cx43) was involved in the neuropathic pain, and Cx43 induced the release of chemokine CXCL12 in bone marrow stromal cells. However, whether spinal Cx43 mediates the production of CXCL12 to participate in the maintenance of BCP is still unknown. Here we showed that Walker 256 tumor cells inoculation into the tibia induced a significant mechanical allodynia, which was accompanied by upregulation of spinal p-Cx43 and CXCL12 expression levels from day 6 to day 18 after inoculation. Spinal Cx43 was mainly expressed in astrocytes, and intrathecal (43)Gap26 (a selective Cx43 blocker) markedly attenuated mechanical allodynia as well as reduced p-Cx43 and CXCL12 expression at day 18 after inoculation. Pre-intrathecal administration of CXCL12 almost abolished the attenuated mechanical allodynia by (43)Gap26. Furthermore, intrathecal injection of anti-CXCL12 neutralizing antibody could ameliorate mechanical allodynia with concomitant inhibition of upregulation of CXCL12 expression, but not influence on p-Cx43 expression. Our results indicate that Cx43 mediates CXCL12 production from spinal dorsal horn in astrocytes to maintain bone cancer pain in rats. These findings may improve our understanding of the underlying mechanisms of BCP and provide a novel target for the treatment of BCP.

Oral Administration of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and Honey Improves the Host Body Composition and Modulates Proteolysis Through Reduction of Tumor Progression and Oxidative Stress in Rats.

Oxidative stress has a dual role in cancer; it is linked with tumorigenic events and host wasting, as well as senescence and apoptosis. Researchers have demonstrated the importance of coadjuvant therapies in cancer treatment, and Aloe vera and honey have immunomodulatory, anticancer, and antioxidant properties. The preventive and therapeutic effects of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and honey in tumor progression and host wasting were analyzed in Walker 256 carcinoma-bearing rats. The animals were distributed into the following groups: C=control-untreated, W=tumor-untreated, WA=treated after tumor induction, A=control-treated, AW=treated before tumor induction, and AWA=treated before and after tumor induction. Proteolysis and oxidative stress were analyzed in the tumor, liver, muscle, and myocardial tissues. The results suggest that the Aloe vera and honey treatment affect the tumor and host by different mechanisms; the treatment-modulated host wasting and cachexia, whereas it promoted oxidative stress and damage in tumor tissues, particularly in a therapeutic context (WA).

cGMP and cGMP-dependent protein kinase I pathway in dorsal root ganglia contributes to bone cancer pain in rats.

STUDY DESIGN: A prospective, randomized experimental research. OBJECTIVE: To demonstrate the role of cGMP (cyclic guanosine monophosphate)-cGKI (cGMP-dependent protein kinase I) pathway in dorsal root ganglia (DRG) in bone cancer pain. SUMMARY OF BACKGROUND DATA: Treating bone cancer pain continues to possess a major clinical challenge because the specific cellular and molecular mechanisms underlying bone cancer pain remain elusive. cGMP and cGMP-dependent protein kinases pathway in DRG plays important role in nerve injury-induced hyperexcitability of DRG neurons, as well as neuropathic pain, however, whether this pathway participates in bone cancer pain is unknown. METHODS: The rat model of bone cancer pain was produced by intramedullary injection of rat breast cancer cells (Walker 256) into right tibia. Thermal hyperalgesia and mechanical allodynia were measured before and after administration of inhibitor of cGMP-cGKs pathway (Rp-8-pCPT-cGMPS). Immunofluorescence and reverse transcription-polymerase chain reaction were used to reflect expression of cGKI in DRG neurons, whereas the concentration of cGMP in DRG was tested using enzyme-linked immunosorbent assay method. Whole-cell patch clamp was used to record the hyperexcitability of small neurons in DRG with or without cGKs inhibitor after tumor cell implantation (TCI). RESULTS: TCI treatment significantly increased the concentration of cGMP in DRG and activity of cGKs in DRG and the spinal cord. TCI treatment also induced upregulation of cGKI messenger ribonucleic acid and protein in DRG, as well as enhanced hyperexcitability in DRG neurons. Spinal administration of Rp-8-pCPT-cGMPS, cGMP-cGKs inhibitor, significantly suppressed TCI-induced activation of cGMP-cGKI signaling, and hyperexcitability of DRG neurons. Meanwhile, in vivo intrathecal delivery of the Rp-8-pCPT-cGMPS significantly prevented and suppressed TCI-induced hyperalgesia and allodynia. CONCLUSION: From these results, we confirm that TCI treatment activates cGMP-cGKI signaling pathway and continuing activation of this pathway in DRG is required for hyperalgesia and/or hyperalgesia and allodynia after TCI treatment. LEVEL OF EVIDENCE: N/A.

Changes in lipid metabolism during Walker 256 tumor growth and the therapeutic effect of hyperthermia.

The dynamics of lipoprotein content during Walker 256 tumor growth in rats was studied. Moderate changes in HDL and LDL were paralleled by significant changes in VLDL level. A 2-fold increase of VLDL in comparison with the intact control was recorded on day 10 of tumor growth. Exposure to total hyperthermia additionally stimulated VLDL synthesis and this parameter increased by 4 times and more in rats with tumors in comparison with controls. This effect of hyperthermia correlated with significant subsequent decrease of rat mortality caused by the lethal effect of the tumor.

Contributions of spinal D-amino acid oxidase to bone cancer pain.

D-Amino acid oxidase (DAAO), a FAD-dependent peroxisomal flavoenzyme that catalyzes oxidation of D-amino acids to hydrogen peroxide, is distributed in the spinal cord almost exclusively expressed within astrocytes. The present study aims to explore potential contributions of spinal DAAO to the development of bone cancer pain and morphine tolerance to analgesia. Tibia inoculation of carcinoma cells produced mechanical allodynia (but not heat hyperalgesia), in synchronous with induction of DAAO expression and DAAO enzymatic activity, as well as activation of spinal astrocytes marked by GFAP. Subcutaneous and intrathecal injection of the specific DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked mechanical allodynia in a dose- and time-dependent manner in tumor-bearing rats, with maximum inhibition of 40-50 %. Multi-daily intrathecal injections of the DAAO gene silencer siRNA/DAAO also yielded anti-allodynic effects by approximately 40 % and the analgesia remained for at least 6 days. Subcutaneous injection of CBIO suppressed the production of spinal hydrogen peroxide and GFAP expression. 7-Day multiple bi-daily injections of CBIO produced anti-allodynia without inducing self-tolerance to analgesia or cross-tolerance to morphine, and concurrent injections of CBIO with morphine produced apparent additive anti-allodynia and completely prevented morphine tolerance in behaviors and spinal expression of µ-opioid receptors. Our results provide the first evidence that spinal DAAO contributes to the development of morphine tolerance to analgesia and bone cancer pain accounting for 40-50 % pain status, probably via production of hydrogen peroxide leading to activation of astrocytes. The unique characterizations of DAAO inhibitors make them a potential for the treatment of cancer pain when they are administered alone or in combination with morphine.

Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats.

It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1ß, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 µg) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 µg, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.

The effects of electroacupuncture at the ST36 (Zusanli) acupoint on cancer pain and transient receptor potential vanilloid subfamily 1 expression in Walker 256 tumor-bearing rats.

BACKGROUND: Several studies have addressed the expression of transient receptor potential vanilloid subfamily 1(TRPV1) playing an important role in the generation of cancer pain. Electroacupuncture (EA) is an effective method of acupuncture shown to attenuate different kinds of pain such as inflammatory, neuropathic, and cancer. In this study, we investigated the effect of EA on cancer pain caused by intraplantar injection of Walker 256 carcinoma cells and cancer-driven TRPV1 expression in the dorsal root ganglions (DRGs). METHODS: Rats were randomly divided into 4 groups: the nontumor cell inoculation group (normal control, n = 8); Walker 256 carcinoma cell inoculation group (tumor control, n = 8); sham point electrical stimulation treatment with Walker 256 carcinoma cell inoculation group (SES, n = 8); EA treatment with Walker 256 carcinoma cell inoculation group (EA, n = 8). The time courses of thermal, mechanical sensitivity, and spontaneous nocifensive behavior were determined. In addition, TRPV1 expression in DRGs was observed by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: Injection of cancer cells decreased the paw withdrawal threshold, increased spontaneous nocifensive behavior, and induced significant thermal hyperalgesia that was attenuated by EA at the ST36 acupoint (2 Hz, 0.3 ms, ≤1 mA). TRPV1 mRNA and protein in DRGs were upregulated in the cancer pain model, and EA at ST36 acupoint counteracted the cancer-driven upregulation of TRPV1 expression in the corresponding DRGs. CONCLUSIONS: EA at ST36 could attenuate cancer-induced pain, at least in part, through suppressing TRPV1 mRNA and protein upregulation in the DRGs.

Involvement of EphB1 receptor/ephrinB1 ligand in bone cancer pain.

In prior studies, Eph/ephrin system was demonstrated to be involved in inflammatory and neuropathic pain modulation. The present study was to investigate whether the spinal Eph/ephrin signaling was involved in modulation of spinal inflammatory cytokines in bone cancer pain (BCP) of rats. BCP was induced by intra-tibial inoculation of Walker 256 mammary gland carcinoma cells. The expressions of EphB1/ephrinB1 in spinal cord (SC) and dorsal root ganglia (DRG) were determined. At 16 days post inoculation, the pain relieving effect and the mRNA levels of inflammatory cytokines were detected after intrathecal administration of EphB1-Fc (blocker of EphB1 receptor, 10µg). The results showed that the EphB1/ephrinB1 expression was significantly increased in SC, but ephrinB1 was decreased in DRG after Walker 256 inoculation. The mechanical allodynia induced by bone cancer was significantly alleviated by intrathecal administration of EphB1-Fc. Furthermore, the RT-PCR analysis showed that the mRNA levels of IL-1ß, IL-6 and TNF-α were significantly increased at 16 days post Walker 256 inoculation and were significantly suppressed by intrathecal administration of EphB1-Fc in SC. We concluded that Eph/ephrin might be involved in the maintenance of mechanical allodynia, via modulating the expression of spinal inflammatory cytokines, in the present rat model of BCP. This study suggested that Eph/ephrin signaling would be a potential target for the treatment of BCP.

Physical exercise and a leucine-rich diet modulate the muscle protein metabolism in Walker tumor-bearing rats.

Leucine-supplemented diet can recover lean body mass and preserve muscle protein mass. Additionally, physical exercise can be an excellent alternative to improve the rehabilitation of cancer patients. Knowing these facts, we examined the effects of a leucine-rich diet with or without physical aerobic exercise on muscle protein metabolism in Walker tumor-bearing rats. Young rats were divided into 4 groups that did or did not perform light aerobic exercise (swim training) and were on a leucine-rich diet or a control diet for 2 mo. After this time, these animals were implanted or not with tumors (subcutaneously) following groups for either control diet or leucine-rich diet fed rats: control, trained, tumor-bearing, and trained tumor-bearing. Twenty-one days after implantation, the tumor growth induced a decrease in the muscle protein synthesis and increased the catabolic process, which was associated with an increase in the expression of the ubiquitin-proteasome subunits (20S, 19S, and 11S). In contrast, the exercise program minimized the muscle degradation process and increased muscle myosin content. Additionally, leucine supplementation also modulated proteasome subunits, especially the 19S and 11S. In summary, the exercise has beneficial effects by reducing tumor growth, leading to an improvement in protein turnover especially when in conjunction with a leucine-rich diet.

Intrathecal injection of anti-CX3CR1 neutralizing antibody delayed and attenuated pain facilitation in rat tibial bone cancer pain model.

This study was designed to investigate the effect of intrathecal injection of anti-CX3CR1 neutralizing antibody on pain behaviors in the rat tibial bone cancer pain model. Syngeneic Walker 256 mammary gland carcinoma cells were injected into the tibia medullary cavity to establish the rat model of bone cancer pain. Ambulatory pain, mechanical hindpaw withdrawal threshold, and latency of paw withdrawal to a thermal stimulus were observed. Haematoxylin/eosin staining was used to observe the bone damage on day 21. Intrathecal injection of anti-CX3CR1 neutralizing antibody both delayed the development of ambulatory pain and hyperalgesia and attenuated established pain facilitation, but had no effects on destruction of bone. Our results suggest that intrathecal injection of anti-CX3CR1 neutralizing antibody delayed and attenuated pain facilitation in the rat tibial bone cancer pain model.

Differences between orofacial inflammation and cancer pain.

Rat models of orofacial cancer exhibit both allodynia and hyperalgesia; however, it is unclear whether cancer-induced pain is secondary to cancer-induced inflammation. To address this question, we compared the effects of an anti-inflammatory drug, indomethacin, on pain and neurochemical changes in the medullary dorsal horn in orofacial inflammation and cancer models. Daily peripheral administration of indomethacin largely suppressed mechanical allodynia and thermal hyperalgesia in the inflammation model. The same procedure suppressed allodynia and hyperalgesia in the cancer model, but the suppression was weak when compared with that in the inflammation model. In the medullary dorsal horn, calcitonin gene-related peptide and substance P levels were significantly increased in the inflammation model, but did not change in the cancer model. These results suggest that pain in the orofacial cancer model is not significantly mediated by cancer-induced peripheral inflammation, although it may have some involvement.

Effect of fish oil supplementation for two generations on changes of lymphocyte function induced by Walker 256 cancer cachexia in rats.

Fish oil supplementation has been shown to improve the cachectic state of tumor-bearing animals and humans. Our previous study showed that fish oil supplementation (1 g per kg body weight per day) for 2 generations had anticancer and anticachetic effects in Walker 256 tumor-bearing rats as demonstrated by reduced tumor growth and body weight loss and increased food intake and survival. In this study, the effect of fish oil supplementation for 2 generations on membrane integrity, proliferation capacity, and CD4/CD8 ratio of lymphocytes isolated from mesenteric lymph nodes, spleen, and thymus of Walker 256 tumor-bearing animals was investigated. We also determined fish oil effect on plasma concentration and ex vivo production of cytokines [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, and IL-10]. Lymphocytes from thymus of tumor-bearing rats presented lower viability, but this change was abolished by fish oil supplementation. Tumor growth increased proliferation of lymphocytes from all lymphoid organs, and fish oil supplementation abolished this effect. Ex vivo production of TNF-alpha and IL-6 was reduced in supplemented animals, but IL-4 and IL-10 secretion was stimulated in both nontumor and tumor-bearing rats. IL-10 and IFN-gamma plasma levels was also decreased in supplemented animals. These results suggest that the anticachetic effects of fish oil supplementation for a long period of time (2 generations) in Walker 256 tumor-bearing rats may be associated to a decrease in lymphocyte function as demonstrated by reduced viability, proliferation capacity, and cytokine production.

Anaerobic exercise reduces tumor growth, cancer cachexia and increases macrophage and lymphocyte response in Walker 256 tumor-bearing rats.

Here, we investigated the effect of jump exercise on tumor growth, cancer cachexia, lymphocyte proliferation and macrophage function in Walker 256 tumor-bearing rats. Male Wistar rats (60 days) were divided into sedentary (C) and exercised (E) groups. Jump training consisted of six sets of 10 jumps in water with overload of 50% of body mass with 1 min of resting, four times per week for 8 weeks. After 6 weeks of training, half of each group was inoculated with 2 x 10(7) cells of Walker 256 tumor. Sedentary tumor-bearing and exercised tumor-bearing are referred to as T and TE, respectively. Tumor weight in the T group was 25 g. These animals display loss of weight, hypertriacylglycerolemia, hyperlacticidemia, depletion of glycogen stores and increase in PIF expression. Jump exercise (TE) induced a significant lower tumor weight, preserves liver glycogen stores, partly prevented the hypertriacylglycerolemia, hyperlacticidemia and, prevented the fall in body weight and reduced PIF expression. Lymphocyte was increased by tumor burden (T) and was higher by including exercise (TE). The same was observed regarding phagocytosis and lysosomal volume. Anaerobic exercise decreases tumor growth, cancer cachexia and increases innate and adaptative immune function.

The action of extracellular NAD+ in the liver of healthy and tumor-bearing rats: model analysis of the tumor-induced modified response.

The chronic inflammatory state induced by cancer is expected to affect the actions of extracellular NAD(+) in the liver because these are largely mediated by eicosanoids. Under this assumption the present work was planned to investigate the influence of the Walker-256 tumor on the action of extracellular NAD(+) on metabolism and hemodynamics in the perfused rat liver. The experiments were done with livers from healthy and tumor-bearing rats with measurements of gluconeogenesis from lactate, pyruvate production, oxygen consumption and portal pressure. A model describing the biphasic effects of NAD(+) was proposed as an auxiliary worktool for interpretation. The Walker-256 tumor modified the responses of metabolism to extracellular NAD(+) by delaying the peak of maximal responses and by prolonging the inhibitory effects. The transient increase in portal perfusion pressure caused by NAD(+) was enhanced and delayed. The model was constructed assuming the mediation of a down-regulator (inhibition), an up-regulator (stimulation) and receptor dessensitization. Analysis suggested that the productions of both the down- and up-regulators were substantially increased and delayed in time in the tumor-bearing condition. Since the regulators are probably eicosanoids, this analysis is consistent with the increased capacity of producing these agents in the chronic inflammatory state induced by cancer.

Metabolic and morphological alterations induced by proteolysis-inducing factor from Walker tumour-bearing rats in C2C12 myotubes.

BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model.

[Hormonal dependency of Walker 256 carcinosarcoma growing in rats].

The particularities of Walker 256 carcinosarcoma growing were studied in rats depending on hormonal background. Rats of lines NISAG and Brattleboro were characterized by the increased and lowered level of endogenous corticosteroids, respectively, in contrast with rats WAG different dynamics of growing tumors. If rats NISAG are not distinguished from rats WAG on the growing tumors, then the tumor grows weakly in the rats of line Brattleboro, and it takes place during the first fortnight only but then begins a regression up to disappearance. Velocity of tumor increasing is slowed in rats of WAG line under adrenalectomy but this effect disappears after introduction of exogenous cortisol. Cortisol introduction does not correct atypical dynamics of tumors in rats Brattleboro.

Effect of a high-intensity exercise training on the metabolism and function of macrophages and lymphocytes of walker 256 tumor bearing rats.

Epidemiologic studies suggest that moderately intense training promotes augmented immune function, whereas strenuous exercise can cause immunosupression. Because the combat of cancer requires high immune function, high-intensity exercise could negatively affect the host organism; however, despite the epidemiologic data, there is a lack of experimental evidence to show that high-intensity training is harmful to the immune system. Therefore, we tested the influence of high-intensity treadmill training (10 weeks, 5 days/week, 30 mins/day, 85% VO(2)max) on immune system function and tumor development in Walker 256 tumor-bearing Wistar rats. The metabolism of glucose and glutamine in lymphocytes and macrophages was assessed, in addition to some functional parameters such as hydrogen peroxide production, phagocytosis, and lymphocyte proliferative responses. The metabolism of Walker 256 cells was also investigated. Results demonstrated that high-intensity training increased the life span of tumor-bearing rats, promoted a reduction in tumor mass, and prevented indicators of cachexia. Several changes, such as a reduction in body weight and food intake and activation of glutamine metabolism in macrophages and lymphocytes induced by the presence of Walker 256 tumor, were prevented by high intensity training. The reduction in tumor growth was associated with an impairment of tumor cell glucose and glutamine metabolism. These data suggest that high-intensity exercise training may be a viable strategy against tumors.

Photodynamic therapy of Walker tumors by multiple laser irradiation.

OBJECTIVE: Photodynamic therapy of Walker tumor after subcutaneous administration of 5-ALA solution using a multiple laser irradiation scheme was monitored by the fluorescence imaging technique to investigate the effectiveness of 5-ALA-PDT. BACKGROUND DATA: Photodynamic therapy (PDT) is a localized cancer treatment based on the selective uptake and retention of photosensitizer at the tumoral level and on the activation of the photosensitizer by a specific wavelength of light, aiming to induce cytotoxic reactions. As a new photosensitizer, the heme precursor 5- aminolevulinic acid has been introduced recently for photodynamic therapy of tumors and precancerous lesions of the skin. It has been shown that the efficacy of topical 5-ALA-PDT is limited for deeper skin tumor by the depth of 5-ALA penetration through the skin. Oral or systemic administration of ALA or the use of different irradiation schemes may improve tumor response to PDT. METHODS: Laser irradiation parameters used in this study were lambda = 635 nm, P = 3 mW, t(exp) = 300 sec, and three sessions. The fluorescence was excitated by monochromatic light of 405 nm. The temporal behavior of PpIX fluorescence was studied by processing and analyzing the fluorescence images acquired just after applying 5-ALA, just before and just after three laser irradiations. RESULTS: The results demonstrate that PpIX is highly selective for tumors areas and a re-accumulation of PpIX appears between laser irradiations. During laser irradiation, the PpIX fluorescence intensity decreases rapidly, reflecting the photodegradation of PpIX. CONCLUSIONS: In conclusion, the use of a multiple laser irradiation scheme, for the activation of reaccumulation of Pp IX (with three steps) is effective for photodynamic therapy of Walker tumor.