AIMS AND BACKGROUND: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. METHODS AND STUDY DESIGN: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die i.v. infusion over 1-2 h for at least 10 days. RESULTS: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. CONCLUSIONS: Our preliminary results should be confirmed in double-blind, placebo controlled studies.

OBJECTIVE:To study the inhibitory effect of Ganoderma lucidum, the extract of chloroform, the extract of ethyl acetate and the remains after two-time extraction on BEL-7402 and MGC-803 cells and their protective effects on HL-7702 cells pre-and post-exposed to cisplatin (DDP) and various doses of 60Co gamma irradiation.

METHOD:The antitumor activity and protective effects on damaged HL-7702 cells induced by radiotherapy and chemotherapy of ganoderma lucidum were determined by MTT technique.

RESULT:The anticancer activity of the extract of chloroform Ganoderma lucidum was the best: at the concentration of 0.125 mg x mL(-1), the inhibitory rate was over 50%. To the HL-7702 cells damaged by DDP, four kinds of extracts didn't exert restoring effect, but the pretreatment with the extract of chloroform reduced the damaged degree significantly. To the 60Co gamma irradiated HL-7702 cells, only the extract of chloroform exerted restoring effect to some extent when exposed to middle or high dose of irradiation. The pre-administration of four kinds of extracts reduced the damaged degree by radiation.

CONCLUSION:The extract of chloroform exerts notable antitumor effects on cancer cells and protective effects on damaged normal cells induced by radiotherapy and chemotherapy.

BACKGROUND: Oxidative stress, resulting from an imbalance between prooxidant and antioxidant systems in favor of the former, largely contributes to immune system deregulation and complications observed in end-stage renal disease (ESRD) and patients treated with hemodialysis. Reactive oxygen species and free radicals are involved in the nephrotoxicity induced by a synthetic anticancer drug cisplatin. METHODS: A comparative study on the nephroprotective effects of antioxidant vitamins (250 and 500 mg/kg, p.o.), vitamin C (ascorbic acid) and vitamin E (alpha-tocopherol), was evaluated using cisplatin (10 mg/kg body wt, i.p.) induced oxidative renal damage in mice. Urea and creatinine in serum were estimated for the renal function. Antioxidant status was estimated in kidney homogenate. RESULTS: We found that both vitamins at 500 mg/kg significantly (P<0.01) protected the nephrotoxicity induced by cisplatin. The cisplatin induced increase of urea and creatinine concentrations were reduced in the vitamins plus cisplatin (250 and 500 mg/kg, p.o.)-treated groups. However the cisplatin induced decline of renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities were increased only in the 500 mg/kg vitamins treated groups. Both vitamins at 250 and 500 mg/kg could increase the concentration of reduced glutathione (GSH) and protected the increase of cisplatin induced lipid peroxidation. CONCLUSIONS: Higher doses of vitamins are effective to protect oxidative renal damage and vitamin C is the better nephroprotective agent than vitamin E. The protection is mediated partially by preventing the decline of renal antioxidant status.

Although cisplatin is a potent anticancer drug, it instigates oxidative and pro-inflammatory reactions which poses significant and distressing clinical symptoms in patients including nausea and vomiting which is related to damage of the gastric mucosa. This study investigated the effects of vitamin C and/or L-carnitine on cisplatin-induced gastric mucosa damage in rat. The rats were allocated into groups (n=5): a control group received distilled water and treatment groups received cisplatin (CIP) alone, cisplatin followed by vitamin C, L-carnitine or their combination. Cisplatin treatment caused disruption of the gastric mucosa histoarchitecture and alter the mucus barrier function in the gastric mucosa. Moreover, stomach tissue from the CIP treated group had increased levels of oxidative stress markers, malondialdehyde and H2O2 levels, and decreased activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalase, glutathione S-transferase and non-antioxidant enzyme, reduced glutathione level. These deleterious events were accompanied by upregulated levels of the pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1beta, and inflammatory infiltration markers, myeloperoxidase and inducible nitric oxide synthase (iNOS). However, administration of both vitamin C and L-carnitine, and not the either of the two showed additive effect in attenuating these toxic effects which were confirm histologically. In conclusion, the combined administration of vitamin C and L-carnitine, but not the single therapy, could prevent the adverse effects of cisplatin on gastric tissues.

Previous studies have presented that Maitake beta-glucan (MD-Fraction) extracted from the fruit body of Grifola frondosa has an anti-tumor effect by activating the immune system. Recently, the stimulating effects of beta-glucans on hematopoiesis were identified as new characteristics of polysaccharides, possibly helping to relieve the immunosuppression which results from chemotherapies. We demonstrated that the production of granulocyte colony-stimulating factor (G-CSF) was significantly enhanced by MD-Fraction (8mg/kg, i.p.) in granulocytopenic model induced in mice using cyclophosphamide (200mg/kg, i.p.). In addition, MD-Fraction induced a biphasic increase in the number of granulocytes in the spleen. The mechanism for the increase in granulocytes on the early phase on day 1 might involve the increased mRNA expression of macrophage inflammatory protein-2 (MIP-2), in the splenic cells, thereby recruiting granulocytes into the spleen. Interestingly, a decline of myeloid progenitors in the bone marrow and an increase in granulocytes in the peripheral blood were observed on day 5, suggesting a mobilization of granulocytes and their progenitors from the bone marrow to the peripheral blood. We confirmed that a possible mechanism in which MD-Fraction promoted the mobilization of granulocytes and their progenitors from the bone marrow is down-regulating the expression of the chemokine receptor, CXCR4, and its ligand, stromal cell-derived factor 1 (SDF-1) in the bone marrow microenvironment. These results reveal a novel function of Maitake beta-glucan that enhances the granulopoiesis and mobilization of granulocytes and their progenitors by stimulating G-CSF production. This finding presents opportunities to develop new therapeutic strategies against the immunosuppression caused by chemotherapies in cancer patients.

BACKGROUND:Chemotherapy, including preoperative chemotherapy, plays an important role in the treatment of esophageal cancer. However, although docetaxel, cisplatin, and fluorouracil (DCF) therapy has a powerful antitumor effect, the associated adverse events make it difficult to maintain the patient's general condition. Oral mucositis is an important adverse effect of chemotherapy, and its severity, frequency, and impact on patient quality of life should not be underestimated. This study evaluated the role of oral cryotherapy for prophylaxis of oral mucositis caused by DCF therapy.

METHODS:We retrospectively examined the incidence and severity of adverse events, including mucositis, in 72 patients with esophageal cancer treated with DCF. Fifty-eight patients received cryotherapy during docetaxel administration and 14 received no cryotherapy.

RESULTS:The incidence of mucositis of all grades and grade 3 was significantly lower in the cryotherapy group compared with the no-cryotherapy group (24.1% vs. 71.4%, P < 0.001 and 0% vs. 28.6%, P = 0.001, respectively). The incidence of anorexia of all grades and grade 3 was also significantly lower in the cryotherapy group (22.4% vs. 57.1%, P = 0.037 and 0% vs. 28.6%, P = 0.010, respectively).

CONCLUSION:Adjunctive oral cryotherapy is effective for the prophylaxis and relief of oral mucositis and anorexia caused by chemotherapy.

BACKGROUND/AIMS:Physical training has beneficial effects on endothelial function and can influence the regeneration of the endothelial cell. We investigated the effect of physical training on cisplatin (CP)-induced acute kidney injury and assessed the impact of training on endothelial structure and function, and on the inflammatory processes in rats.

METHODS:We injected male Wistar rats subjected to previous physical training in treadmill running (trained, TR) or not (sedentary, SED) with CP (5 mg/kg) (TR+CP and SED+CP groups, respectively). Five days after the injections, blood and urine samples were collected to evaluate renal function and kidneys were harvested for morphological, immunohistochemical, enzyme-linked immunosorbent assay, and analysis of nitric oxide (NO) levels.

RESULTS:Rats treated with CP showed increased levels of plasma creatinine and sodium and potassium fractional excretion. These alterations were associated with increase in tubulointerstitial lesions and macrophage number, reduction of endothelial cells, and increased VEGF, vimentin, andα-smooth muscle actin expression in the outer renal medulla in the SED+CP group. We also found increased levels of renal IL-1β and increased excretion of monocyte chemoattractant protein-1 and transforming growth factor-β compared with controls. These changes were milder in trained rats, associated with increased levels of renal tissue NO, and increased expression of p-eNOS and stromal cell-derived factor-1α (a chemokine involved in kidney repair) in the kidneys of CP-injected trained rats.

CONCLUSIONS:The protective effect of previous training in CP-treated rats was associated with reduced endothelial cell lesions and increased renal production of NO in trained rats.

Cisplatin-induced nephrotoxicity is a serious adverse effect that limits the use of cisplatin in cancer patients. In the present study, we investigated the protective effect of lanostane triterpenoids (1-10) isolated from the ethanolic extract of Poria cocos Wolf against cisplatin-induced cell death in LLC-PK1 kidney tubular epithelial cells. Treatment of cisplatin induced significant cell death, which was suppressed by treatment with dehydroeburicoic acid monoacetate (1) and 3β-acetoxylanosta-7,9(11),24-trien-21-oic acid (9). Compound 1 exhibited the highest efficacy among the tested compounds and was thus subjected to further mechanistic studies. The increase in the percentage of apoptotic cells induced by cisplatin reduced by 4.3% after co-treatment of cells with compound 1 (50 and 100μM). Furthermore, phosphorylation of the mitogen-activated protein kinases JNK, ERK, and p38, and caspase-3, which characterize oxidative stress-mediated apoptosis, increased significantly after treatment with cisplatin, and decreased after treatment with compound 1. These resultsindicate that the renoprotective effects of compound 1 may be mediated by its anti-apoptotic activity.

BACKGROUND:Gynecological malignancies represent a major cause of death in women and are often treated with platinum-based regimens. Patients undergoing chemotherapy suffer from alterations in nutritional status which may worsen gastrointestinal (GI) toxicities, quality of life and affect the overall prognosis. Indeed, assuring a good nutritional status and limiting toxicities during treatment are still major goals for clinicians.

AIM:To assess the role of Mediterranean Diet (MD) in reducing GI toxicities in patients with gynecological cancers treated with platinum-based regimens.

METHODS:We conducted an observational study on 22 patients with gynecological tumors treated with a platinum-based chemotherapy at Candiolo Cancer Institute FPO/IRCCS between January 2018 and June 2018. The food and frequency (FFQ) and the Patient-Reported Outcomes Common Terminology Criteria For Adverse Events (PRO-CTCAE) questionnaires were administered at baseline and at every Day 1 of each cycle. To evaluate the differences in GI toxicities the study population was divided in two groups according to the currently validated Mediterranean Diet Serving Score (MDSS) at baseline.

RESULTS:Patients with high MDSS reported a trend toward lower GI toxicities according to PRO-CTCAE at each timepoint (first evaluation:= 0.7; second:= 0.52; third:= 0.01). In particular, difference in nausea frequency and gravity (<0.001), stomach pain frequency and gravity (= 0.01 and= 0.02), abdomen bloating frequency and gravity (= 0.02 and= 0.03), and interference with daily activities (= 0.02) were highly statistically significant at the end of treatment. More than 60% of patients changed their food habits during chemotherapy mainly because of GI toxicities. A higher reduction of food intake, both in terms of caloric (= 0.29) and of single nutrients emerged in the group experiencing higher toxicity.

CONCLUSION:Our results show that adherence to MD possibly reduces GI toxicity and prevents nutritional status impairment during chemotherapy treatment. Bigger studies are needed to confirm our results.

Acetyl-L-carnitine (ALC) improves non-oncological neuropathies. We tested oral ALC (1 g tid) for 8 weeks in 25 patients with neuropathy grade 3 (common toxicity criteria--CTC) during paclitaxel or cisplatin therapy, or grade 2 persisting for at least three months after discontinuing the drugs. An independent neurologist assessed patients before and after ALC. All patients except one reported symptomatic relief, and only two described grade 1 nausea. The sensory neuropathy grade improved in 15 of 25 (60%), and motor neuropathy in 11 of 14 patients (79%). Total neuropathy score (TNS) that included neurophysiological measures improved in 23 (92%). Amelioration of sensory amplitude and conduction velocity (sural and peroneal nerves) was measured in 22 and 21 patients, respectively. Symptomatic improvement persisted in 12 of 13 evaluable patients at median 13 months after ALC. In view of its effect in improving established paclitaxel- and cisplatin-neuropathy, we recommend ALC testing in preventing progression or revert symptoms during neurotoxic chemotherapy.