Chemotherapy In Rats Research Articles

Danggui Jixueteng decoction for the treatment of myelosuppression after chemotherapy: A combined metabolomics and network pharmacology analysis

ObjectiveThis study aimed to explore the mechanism of the Danggui Jixueteng decoction (DJD) in treating Myelosuppression after chemotherapy (MAC) through network pharmacology and metabolomics. MethodsWe obtained the chemical structures of DJD compounds from TCMSP and PubMed. SwissTargetPrediction, STITCH, CTD, GeneCards, and OMIM were utilized to acquire component targets and MAC-related targets. We identified the key compounds, core targets, main biological processes, and signaling pathways related to DJD by constructing and analyzing related networks. The main active compounds and key proteins of DJD in treating AA were confirmed by molecular docking. A MAC rat model was established through intraperitoneal injection of cyclophosphamide to confirm DJD's effect on the bone marrow hematopoietic system. Untargeted metabolomics analyzed serum metabolite differences between MAC rats and the control group, and before and after DJD treatment, to explore DJD's mechanism in treating MAC. ResultsOf the 93 active compounds identified under screening conditions, 275 compound targets and 3113 MAC-related targets were obtained, including 95 intersecting targets; AKT1, STAT3, CASP3, and JUN were key proteins in MAC treatment. The phosphatidylinositol-3-kinase/RAC-alpha serine/threonine-protein kinase (PI3K/AKT) signaling pathway may play a crucial role in MAC treatment with DJD. Molecular docking results showed good docking effects of key protein AKT1 with luteolin, β-sitosterol, kaempferol, and glycyrrhizal chalcone A. In vivo experiments indicated that, compared to the model group, in the DJD group, levels of WBCs, RBCs, HGB, and PLTs in peripheral blood cells, thymus index increased, spleen index decreased, serum IL-3, GM-CSF levels increased, and IL-6, TNF-α, and VEGF levels decreased (p < 0.01); the pathological morphology of femoral bone marrow improved. Eleven differential metabolites were identified as differential serum metabolites, mainly concentrated in phenylalanine, tyrosine, and tryptophan biosynthesis pathways, phenylalanine metabolism, and arachidonic acid metabolism. ConclusionThis study revealed that DJD's therapeutic effects are due to multiple ingredients, targets, and pathways. DJD may activate the PI3K/AKT signaling pathway, promote hematopoietic-related cytokine production, regulate related metabolic pathways, and effectively alleviate cyclophosphamide-induced myelosuppression after chemotherapy in rats.

Nutritional Support of Crocin on Neurobehavioral Disabilities Induced by Cisplatin-Based Chemotherapy in Rats.

Cisplatin, a chemotherapy drug containing platinum, is considered a neurotoxic agent. On the other hand, crocin, the primary component of saffron, possesses neuroprotective and antioxidant properties. In this study, 28 healthy adult male Wistar rats weighing 200-250g were used (6-7 weeks old). Rats were divided into a control group (Ctr), a crocin group (Cro), a cisplatin group (Cis), and a crocin with cisplatin group (Cro + Cis). Rotarod, open field, and shuttle box tests were performed to assess balance, explorative behavior, and avoidance memory. After behavioral testing, the hippocampus was extracted to analyze oxidative stress parameters such as GPx (glutathione peroxidase), SOD (superoxide dismutase), CAT (catalase), and MDA (malondialdehyde) activity. Shuttle box, rotarod, and open field results showed that crocin can substantially mitigate the deleterious effects of cisplatin on avoidance memory, explorative behavior, motor coordination, and balance. Crocin was also able to effectively avoid the negative effects of cisplatin on MDA, GPx, and CAT during the assessment of oxidative indicators, while the beneficial effect of crocin on cisplatin was not statistically significant in terms of SOD level. In conclusion, since free radicals produced by cisplatin are a contributing factor to memory loss and movement disorders, crocin, owing to its antioxidant properties, improved passive avoidance learning as well as motor activity.

Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation

Dose adjustment based on renal function is essential in S-1, which contains the 5‑fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats. AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours. No alterations in the area under the plasma concentration–time curve (AUC0-24h ) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy. To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.

Resveratrol ameliorates oxaliplatin-induced neuropathic pain via anti-inflammatory effects in rats.

Oxaliplatin (OXA) is a common chemotherapy drug and exhibits clinical activity in several cancer types. Its anticancer clinical effect is frequently accompanied by neurotoxicity. The symptoms include paresthesia and pain, which adversely affect the quality of life of patients. In the present study, five consecutive intraperitoneal injections of 4 mg/kg OXA were used to mimic chemotherapy in rats. OXA administration induced mechanical allodynia, activated spinal astrocytes and triggered the inflammatory response. To explore potential therapeutic options for OXA-induced neuropathic pain, resveratrol (Res) was intrathecally injected into the spinal cord of OXA-treated rats. Paw withdrawal threshold values of OXA-treated rats were increased, indicating an antinociception effect of Res on OXA-induced pain. Additionally, Res treatment reduced the levels of glial fibrillary acidic protein, TNF-α, IL-1β and NF-κB, which were upregulated in OXA-treated rats (compared with control). Furthermore, Auto Dock data showed that Res binds to cyclooxygenase-2 (COX-2) through six hydrogen bonds. Western blot analysis and reactive oxygen species (ROS) assays indicated that Res treatment decreased COX-2 expression and suppressed ROS production. In summary, intrathecal injection of Res reduced the spinal COX-2-mediated ROS generation and inflammatory reaction, suppressed astrocytic activation, and alleviated OXA-induced neuropathic pain.

Rescuing Behavioral Impairment after Doxorubicin Chemotherapy in Rats

Chemotherapy regimens have been extensively used for the treatment of various types of cancers. Despite the effectiveness of this treatment, clinical use of chemotherapeutic agents often produces negative side effects like deficits in cognition and memory, delayed processing speed, and executive function. This condition is widely recognized as chemotherapy‐induced cognitive impairment or “Chemo brain.” Our study aimed to identify the neurobiological mechanisms possibly responsible for this cognitive impairment. We examined the effects of chronic treatment with the chemotherapeutic drug Doxorubicin on cognitive impairment. Doxorubicin is a reactive oxygen species‐producing antineoplastic Anthracycline agent that adversely affects hippocampal neurogenesis, causes neuro‐inflammation, and induces apoptosis. Baseline activity data were collected and then twelve young female Long Evans hooded rats were randomly assigned to receive either Doxorubicin (6mg/kg) or 0.9% saline given intraperitoneally, once weekly for four weeks. After treatment, rats were assessed on the string‐pulling task, the bar walk test, and open field test. Two individuals blind to the treatment calculated the average time duration, number of attempts to pull the string, number of misses, total number of mouth contacts before and after treatment for the string‐pulling task, number of deep slips, slight slips, and the total number of slips for the bar walk test. Similarly, the number of entries to the center, number of entries to the corners, time spent at the center vs corner, and latency to first enter and exit the center was calculated for the open field test and compared between two groups. No significant differences were detected between Dox‐treated and Control rats on any measure, which suggests that the Dox‐treatment produced little or no significant peripheral neuropathy that disrupted performance on the motor tasks we used and did not induce significant anxiety in our rats. Immuno‐histochemical analyses of brain tissues is ongoing to examine markers of neurogenesis and neuro‐inflammation.

Assessment role of total phenols and flavonoids extracted from Pleurotus columbinus mushroom on the premature ovarian failure induced by chemotherapy in rats

BackgroundMany species of mushroom contain an assortment of free radical scavengers (Phenolics and Flavonoids compounds) that have made them nutritionally beneficial and a source of expansion of drug production. In this study, we examined the preventive and remedial role of total phenol extract from Pleurotus columbines (TP) in alleviating the consequences of cyclophosphamide (CTX) on the ovaries of female rats. Rats were randomly assigned to four groups: healthy controls, cyclophosphamide (CTX), received a TP (100 mg/kg) orally daily for 14 days and curative group: CTX-TP, we determined and identified a total phenol from a mushroom extract and examined it as an antioxidant agent. To investigate the therapeutic influence, it was administrated 2 weeks after CTX. To assess the impact of TP on ovarian damage caused by CTX, ovarian hormone tests were performed such as luteinizing hormone (LH), 17-β-estradiol (E2), and anti-mullerian hormone (AMH). Besides, follicle-stimulating hormone (FSH) in serum was evaluated, and histopathological analysis of the ovary was examined. ResultsThis study indicates that treatment with TP decreased the severity of cyclophosphamide-induced ovary injury by reducing inflammation and apoptotic effects and increasing the activity of antioxidants. ConclusionsTP could be used to alleviate cyclophosphamide-induced ovary injury.

Assessing Behavioral Impairment after Doxorubicin Chemotherapy in Rats

Chemotherapy has been associated with deficits in cognition and memory, delayed processing speed and executive function which may remain in patients as a long-term neurological effects. In addition, it also causes the disruption of hippocampal cell proliferation and neurogenesis, increased oxidative stress, and disruption in white matter. The cellular mechanisms linked with these side effects are poorly understood until now. Doxorubicin is Anthracycline agent that adversely affects the hippocampal neurogenesis and induces apoptosis by increasing oxygen radicals. It is considered first line therapy treatment for the most common cancers like breast, ovarian, and bladder. Young adult female Long Evans Hooded rats were divided into Doxorubicin treated (6mg/kg IP injection; once weekly for 4 weeks) and control groups (IP injection of sterile 0.9% saline on same schedule). We utilized the string pulling task, skilled ladder rung walking task, and other standard cognitive tests. We also performed immunohistochemistry to examine markers of inflammation related to chemotherapy and the extent to which chemotherapy would affect the process of neurogenesis. The results of the experiment we performed will be presented at the meeting and represent preliminary data for future studies.

β-Catenin signaling is important for osteogenesis and hematopoiesis recovery following methotrexate chemotherapy in rats.

Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the β-catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once-daily injections, 0.75 mg/kg) with/without β-catenin inhibitor indocyanine green (ICG)-001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity. In MTX-treated rats, ICG suppressed bone volume recovery on Day 11 after the first MTX injection. ICG exacerbated MTX-induced decreases on Day 9 osteoblast numbers on bone surfaces, their formation in vitro from bone marrow stromal cells (osteogenic differentiation/mineralization), as well as expression of osteogenesis-related markers Runx2, Osx, and OCN in bone, and it suppressed their subsequent recoveries on Day 11. On the other hand, ICG did not affect MTX-induced increased osteoclast density and the level of the osteoclastogenic signal (RANKL/OPG expression ratio) in bone, suggesting that ICG inhibition of β-catenin does nothing to abate the increased bone resorption induced by MTX. ICG also attenuated bone marrow cellularity recovery on Day 11, which was associated with the suppressed recovery of CD34+ or c-Kit+ hematopoietic progenitor cell contents. Thus, β-catenin signaling is important for osteogenesis and hematopoiesis recoveries following MTX chemotherapy.

Comparison of photobiomodulation using either an intraoral or an extraoral laser on oral mucositis induced by chemotherapy in rats.

The aim of the present study was to compare the effect of intraoral (IO) and extraoral (EO) diode laser irradiation on oral mucositis (OM) induced by 5-fluorouracil (5-FU) in rats. Animals (n= 78) were divided into the following groups: negative control (NC), positive control (PC), IO 6J/cm2, EO with 6J/cm2 (EO 6J/cm2), and 12J/cm2 (EO 12J/cm2). OM was induced with an intraperitoneal injection of 5-FU and scarification of the buccal mucosa. Over the following 14days, animals received photobiomodulation (PBM) daily. Clinical and histological evaluation was done by scores at days 8, 10, and 14. The redox state was evaluated by reactive species levels, antioxidant network, and immunohistochemistry analysis. Clinically, on day 8, PBM groups showed lower scores of OM with EO 6J/cm2 presenting a significantly lower degree compared to PC (p< 0.05). On days 10 and 14, all PBM groups exhibited improvement of OM compared to PC (p< 0.01). On day 8, all PBM groups exhibited an accelerated healing process compared to PC (p< 0.01) and reduction of reactive species (p< 0.001). Also, all PBM groups demonstrated higher levels of antioxidant GPx compared to PC (p< 0.001). Analysis of nitrotyrosine revealed that on day 14, this protein damage marker was significantly reduced in the EO 6J/cm2 group (p> 0.05). An EO diode laser protocol promoted positive effects in the clinical, histopathological, and redox state in OM induced by 5-FU in rats. Among the EO protocols, EO 6J/cm2 showed the most encouraging results.

Effects of melatonin on colonic anastomosis healing following chemotherapy in rats.

This study aimed to investigate the effects of melatonin on the healing of colon anastomosis following chemotherapy. 32 rats were randomised into four groups: (a) control group, which underwent sigmoid colon transection and primary anastomosis; (b) melatonin group, which received melatonin daily following anastomosis; (c) 5-fluorouracil (5-FU) group, which received 5-FU for five days prior to anastomosis; and (d) 5-FU+melatonin group, which received 5-FU for five days prior to anastomosis and melatonin daily following anastomosis. The rats were sacrificed on Postoperative Day 7 and anastomotic bursting pressures were measured. The anastomotic segment was extracted for hydroxyproline, luminol and lucigenin measurement and histopathological examination. Blood samples were obtained from the vena cava for measurement of tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) plasma levels. Compared to the 5-FU group, bursting pressures of anastomosis and hydroxyproline levels were significantly higher, while luminol and lucigenin levels were significantly lower, in the control and 5-FU+melatonin groups. In addition, TNF-α and IL-1β plasma levels were significantly lower in the control and 5-FU+melatonin groups than in the 5-FU group. Histopathological examination showed a significant decrease in inflammation and necrosis formation in the melatonin group when compared to the control group. The positive effect of melatonin was also seen in the rats that received 5-FU. Our study results showed that the adverse effects of chemotherapy on the mechanical, biochemical and histopathological parameters of anastomosis healing were attenuated through melatonin treatment.

Post-treatment with cotinine improved memory and decreased depressive-like behavior after chemotherapy in rats

Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." Cotinine, the main derivative of nicotine, improved visual and spatial working memory and decreased depressive-like behavior in an animal model of chemotherapy-induced cognitive impairment. In this study, we investigated the effect of cotinine on weight gain, locomotor activity, cognitive abilities and depressive-like behavior in rats treated with the chemotherapy mix, cyclophosphamide, methotrexate and 5-fluorouracil. Locomotor activity and depressive-like behavior were assessed using the rotarod and Porsolt's tests, respectively. Changes in cognitive abilities were determined using the novel place recognition test. Female rats treated with cotinine after chemotherapy, recovered weight faster, showed superior cognitive abilities and lower levels of depressive-like behavior than chemotherapy, vehicle-treated rats. This evidence suggests that treatment with cotinine may facilitate the recovery and diminish the cognitive consequences of chemotherapy.

Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats.

Purpose To determine the feasibility of using intraesophageal radiofrequency (RF) hyperthermia to enhance local chemotherapy in a rat model with orthotopic esophageal squamous cancers. Materials and Methods The animal protocol was approved by the institutional animal care and use committee and the institutional review board. Human esophageal squamous cancer cells were transduced with luciferase lentiviral particles. Cancer cells, mice with subcutaneous cancer esophageal xenografts, and nude rats with orthotopic esophageal cancers in four study groups of six animals per group were treated with (a) combination therapy of magnetic resonance imaging heating guidewire-mediated RF hyperthermia (42°C) plus local chemotherapy (cisplatin and 5-fluorouracil), (b) chemotherapy alone, (c) RF hyperthermia alone, and (d) phosphate-buffered saline. Bioluminescent optical imaging and transcutaneous ultrasonographic imaging were used to observe bioluminescence signal and changes in tumor size among the groups over 2 weeks, which were correlated with subsequent histologic results. The nonparametric Mann-Whitney U test was used for comparisons of variables. Results Compared with chemotherapy alone, RF hyperthermia alone, and phosphate-buffered saline, combination therapy with RF hyperthermia and chemotherapy induced the lowest cell proliferation (relative absorbance of formazan: 23.4% ± 7, 44.6% ± 7.5, 95.8% ± 2, 100%, respectively; P < .0001), rendered the smallest relative tumor volume (0.65 mm3 ± 0.15, P < .0001) and relative bioluminescence optical imaging photon signal (0.57 × 107 photons per second per square millimeter ± 0.15, P < .001) of mice with esophageal cancer xenografts, as well as the smallest relative tumor volume (0.68 mm3 ± 0.13, P < .05) and relative photon signal (0.56 × 107 photons per second per square millimeter ± 0.11. P < .001) of rat orthotopic esophageal cancers. Conclusion Intraesophageal RF hyperthermia can enhance the effect of chemotherapy on esophageal squamous cell cancers. © RSNA, 2016.

Supplementation with Fish Oil and Genistein, Individually or in Combination, Protects Bone against the Adverse Effects of Methotrexate Chemotherapy in Rats

Cancer chemotherapy has been shown to induce long-term skeletal side effects such as osteoporosis and fractures; however, there are no preventative treatments. This study investigated the damaging effects of anti-metabolite methotrexate (MTX) subcutaneous injections (0.75 mg/kg BW) for five days and the potential protective benefits of daily oral gavage of fish oil at 0.5 mL/100 g BW (containing 375 mg of n-3 PUFA/100 g BW), genistein (2 mg/100 g BW), or their combination in young adult rats. MTX treatment alone significantly reduced primary spongiosa height and secondary spongiosa trabecular bone volume. Bone marrow stromal cells from the treated rats showed a significant reduction in osteogenic differentiation but an increase in adipogenesis ex vivo. Consistently, stromal cells had significantly higher mRNA levels of adipogenesis-related proliferator activator activated receptor-γ (PPAR-γ) and fatty acid binding protein (FABP4). MTX significantly increased the numbers of bone-resorbing osteoclasts and marrow osteoclast precursor cell pool while significantly enhancing the mRNA expression of receptor activator for nuclear factor kappa B ligand (RANKL), the RANKL/osteoprotegerin (OPG) ratio, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the bone. Supplementary treatment with fish oil and/or genistein significantly preserved trabecular bone volume and osteogenesis but suppressed MTX-induced adipogenesis and increases in osteoclast numbers and pro-osteoclastogenic cytokine expression. Thus, Fish oil and/or genistein supplementation during MTX treatment enabled not only preservation of osteogenic differentiation, osteoblast number and bone volume, but also prevention of MTX treatment-induced increases in bone marrow adiposity, osteoclastogenic cytokine expression and osteoclast formation, and thus bone loss.

Tumor and non-tumor tissues differential oxidative stress response to supplemental DHA and chemotherapy in rats

Developing approaches that will increase the selectivity of anticancer drugs remains a challenge. Docosahexaenoic acid (DHA) has the potential to increase tumor sensitivity to chemotherapy with no sensitization of normal tissues. This study was aimed at exploring the mechanism involved in this differential sensitization with a focus on oxidative stress, one of the main determinants involved in DHA enhancement of anthracycline-based chemotherapy. In a previously validated model of chemically induced mammary tumors in rats where supplemental DHA sensitized tumors to epirubicin, DHA level, lipid hydroperoxides (LPO), total antioxidant activity, glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were measured in tumors, intestine, liver, and heart in rats treated with DHA+epirubicin and in control rats (palm oil, no chemotherapy). At baseline, the level of LPO was similar in tumors, liver, heart, and small intestine. The proportion of DHA was higher in non-tumor tissues compared to tumors (liver or heart, p < 0.0001; intestine, p = 0.01). DHA and epirubicin induced a significant increase in LPO in tumors (p = 0.03), but no increase was detected in liver, heart, or intestine. The difference in LPO production between these tissues was associated with differences in their antioxidant defenses. In tumors, the adjustment of GPx activity was possible but limited, and no adjustment of their total antioxidant and SOD activities was observed compared to other tissues. Supplementing DHA during an anthracycline-based chemotherapy induced a selective increase of LPO in tumors. This selectivity might result from a differential handling of oxidative stress between tumor and non-tumor tissues.

Orally administered emu oil decreases acute inflammation and alters selected small intestinal parameters in a rat model of mucositis

Mucositis resulting from cancer chemotherapy is a serious disorder of the alimentary tract. Emu oil has demonstrated anti-inflammatory properties in animal models of arthritis and wound healing; however, its effects on the intestine remain unknown. We investigated emu oil for its potential to decrease the severity of mucositis in a rat model. Female Dark Agouti rats (110-150 g) were orogastrically gavaged with emu oil (0.5 or 1 ml) or water (1 ml) for 5 d before intraperitoneal injection of 5-fluorouracil (5-FU, 150 mg/kg) or saline (control), and this was continued up to the day of sacrifice (48, 72 and 96 h post 5-FU administration). Histological (villus height, crypt depth (CD) and disease severity score) and biochemical (myeloperoxidase (MPO) activity) parameters were determined in intestinal tissues collected at sacrifice. Sucrase activity in vivo was quantified by the sucrose breath test. Activated neutrophil activity (MPO) in the ileum was significantly decreased by emu oil (0.5 ml, 451 (sem 168) U/g and 1 ml, 503 (sem 213) U/g) compared with 5-FU-treated controls (1724 (sem 431) U/g) 96 h post 5-FU administration. There were also significant increases in CD (152 (sem 8) microm) in the ileum of rats that received 1 ml emu oil at 96 h compared with 5-FU-treated controls (CD (106 (sem 12) microm)). Emu oil did not affect sucrase activity. Emu oil decreased acute ileal inflammation, and improved mucosal architecture in the intestine during recovery from chemotherapy in rats. Further studies investigating the potential benefits of emu oil as a nutritional supplement for the treatment of intestinal disorders are indicated.

Single and combined supplementation of glutamine andn-3 polyunsaturated fatty acids on host tolerance and tumour response to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11)/5-fluorouracil chemotherapy in rats bearing Ward colon tumour

Prior reports suggest that during irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin; CPT-11) chemotherapy in laboratory rats, the anti-tumour efficacy and diarrhoea toxicity could be modulated by n-3 PUFA and glutamine, respectively. We further examined how these two dietary elements, when provided individually and in combination, would affect the efficacy of a cyclical regimen of CPT-11/5-fluorouracil (5-FU), an accepted combination regimen for colorectal cancer. Prior to initiating chemotherapy, diets enriched either with glutamine (2 %, w/w total diet) or n-3 PUFA (0.88 %, w/w total diet) alone, inhibited Ward colon tumour growth (P < 0.05). These diets also completely or partially normalized the changes in peripheral leucocyte counts associated with the tumour-bearing state (e.g. neutrophil proportion/concentration and lymphocyte proportion). During chemotherapy, either glutamine- or n-3 PUFA-enriched diet enhanced tumour chemo-sensitivity, and reduced body weight loss, anorexia and muscle wasting (v. animals fed control diet, P < 0.05). Surprisingly, providing both glutamine and n-3 PUFA together did not confer a greater benefit on tumour inhibition either in the presence or absence of chemotherapy; individual benefits associated with single treatments, particularly in respect to host nutritional status (i.e. body weight, food intake and muscle weight) and immune (peripheral leucocyte counts) features were instead partially or completely lost when these two nutrients were combined. These results draw into question the common assumption that there are additive or synergistic benefits of combinations of nutrients, which are beneficial on an individual basis, and suggest that co-supplementation with glutamine and n-3 PUFA is not indicated during chemotherapy with CPT-11 and 5-FU.

Role of frequency and mechanical index in ultrasonic-enhanced chemotherapy in rats

The therapeutic effect of ultrasound and micellar-encapsulated doxorubicin was studied in vivo using a tumor-bearing rat model with emphasis on how tumor growth rate is affected by ultrasonic parameters such as frequency and intensity. This study employed ultrasound of two different frequencies (20, 476 kHz) and two pulse intensities, but identical mechanical indices and temporal average intensities. Ultrasound was applied weekly for 15 min to one of two bilateral leg tumors (DHD/K12/TRb colorectal epithelial cell line) in the rat model immediately after intravenous injection of micelle-encapsulated doxorubicin. This therapy was applied weekly for 6 weeks. Results showed that tumors treated with drug and ultrasound displayed, on average, slower growth rates than non-insonated tumors (P = 0.0047). However, comparison between tumors that received 20 or 476-kHz ultrasound treatments showed no statistical difference (P = 0.9275) in tumor growth rate. Application of ultrasound in combination with drug therapy was effective in reducing tumor growth rate, irrespective of which frequency was employed.

Nutritional Modulation of Antitumor Efficacy and Diarrhea Toxicity Related to Irinotecan Chemotherapy in Rats Bearing the Ward Colon Tumor

To evaluate and compare the influence of dietary elements on cancer progression, chemotherapy efficacy, and toxicity, particularly severe, late-onset diarrhea related to irinotecan (CPT-11) treatment. We used laboratory rats fed a standardized basal diet, Ward colon tumor, and CPT-11 therapy for the study of CPT-11-induced diarrhea. Dietary interventions were selected from nutrients already established to modify other forms of colitis and which have been hypothesized to mitigate chemotherapy-induced gastrointestinal injury (glutamine, n-3 fatty acids, prebiotic oligosaccharides). Animals adapted to test diets were treated with CPT-11 at the maximum tolerated dose (125 mg/kg x 3 days) and diarrhea was followed continuously for 1 week. The inclusion of n-3 fatty acids in the diet (5%, w/w of total fat) suppressed tumor growth and enhanced CPT-11's efficacy; this treatment did not affect the incidence or severity of diarrhea. By contrast, oral glutamine bolus (0.75 g/kg) administered prior to each CPT-11 treatment reduced the incidence of severe diarrhea (34.1 +/- 4.7% versus 53.8 +/- 4.2%, P < 0.005) and decreased the area under the curve of diarrhea score (16.5 +/- 1.0 versus 18.8 +/- 0.5, P < 0.05). Identical results were obtained with i.v. bolus glutamine administration. Glutamine treatment did not alter CPT-11's antitumor efficacy. The addition of prebiotic oligosaccharides to the diet (8%, w/w of diet) did not mitigate the severity of diarrhea, and it raised the activity of beta-glucuronidase in cecal contents, a key bacterial enzyme mediating CPT-11-related intestinal toxicity. Our experiments suggest that glutamine and n-3 fatty acids might be potentially useful adjuncts to CPT-11 treatment.

Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats

To investigate the effects of granulocyte-colony stimulating factor (G-CSF) on peritoneal defense mechanisms and bacterial translocation after systemic 5-Fluorouracil (5-FU) administration. Thirty Wistar albino rats were divided into three groups; the control, 5-FU and 5-FU + G-CSF groups. We measured bactericidal activity of the peritoneal fluid, phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, total peritoneal cell counts and cell types of peritoneal washing fluid. Bacterial translocation was quantified by mesenteric lymph node, liver and spleen tissue cultures. Systemic 5-FU reduced total peritoneal cell counts, neutrophils and macrophage numbers. It also altered bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. 5-FU also caused significant increase in frequencies of bacterial translocation at the liver and mesenteric lymph nodes. G-CSF decreased bacterial translocation, it significantly enhanced bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. It also increased total peritoneal cell counts, neutrophils and macrophage numbers. Systemic 5-FU administration caused bacterial translocation, decreased the bactericidal activity of peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. G-CSF increased both bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, and prevented the bacterial translocation. We conclude that intraperitoneal GCSF administration protects the effects of systemic 5-FU on peritoneal defense mechanisms.

Vitamin E but not St. John’s wort mitigates leukopenia caused by cancer chemotherapy in rats

Dietary supplements are used by most patients with cancer. As nutraceuticals can interact with many drugs, this study investigated the effect of herbal remedies and vitamins on the toxicity of representative cancer chemotherapeutic agents. Fisher 344 rats were fed a standard cereal-based diet or the same diet with additional vitamin E in low (50 mg/kg) or high (750 mg/kg) concentrations, or with added St. John's wort (400 mg/kg). The LD50 was determined after the administration of chemotherapy drugs. Neither low or high vitamin E supplements nor St. John's wort significantly changed the LD50 for doxorubicin, docetaxel, or cyclophosphamide. The nadir white blood cell (WBC) count was significantly higher (P = 0.004) after docetaxel in rats supplemented with low-dose vitamin E, but the drop in WBC count from initial to nadir levels (Nfall) was greater in rats fed a diet containing high vitamin E supplementation (P = 0.04). Similarly, the Nfall was greater in the standard and high vitamin E dietary groups than in the low vitamin E group after cyclophosphamide (P = 0.03). No effect of vitamin E or St. John's wort supplementation occurred on doxorubicin pharmacokinetics. Neither vitamin E nor St. John's wort had an important effect on the mitochondrial deoxyribonucleic acid (DNA) damage caused by either doxorubicin or docetaxel. These data suggest that the leucopenia caused by some chemotherapeutic agents can be modified by dietary supplementation with vitamin E, but the effect seems to be dose-dependent. St. John's wort had neither a beneficial nor a detrimental effect on chemotherapy-induced toxicity.