Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

This study evaluated the toxicity profiles of temozolomide in the treatment of malignant glioma as either concurrent or adjuvant chemotherapy. We retrospectively reviewed the medical records of 300 malignant glioma patients treated with temozolomide in two medical institutions in Korea between 2004 and 2010. Two hundred nine patients experienced a total of 618 toxicities during temozolomide therapy. A total of 84.8% of the 618 toxicities were Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or 2, while 15.2% were grade 3 or 4. Among the hematologic toxicities, thrombocytopenia (13.7%), anemia (11.0%), and AST/ALT increases (7.0%) were common. Among the non-hematologic toxicities, nausea (44.3%), vomiting (37.0%), and anorexia (14.3%) were the three most common toxicities. There was no mortality due to temozolomide. Although temozolomide showed many types of toxicities, the majority of the toxicities were tolerable and of lower grade. Gastrointestinal troubles are the most common toxicities in Korean patients treated with temozolomide.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anorexia/etiology ; Antineoplastic Agents, Alkylating/adverse effects/*therapeutic use ; Brain Neoplasms/*drug therapy/pathology/radiotherapy ; Dacarbazine/adverse effects/*analogs & derivatives/therapeutic use/toxicity ; Female ; Glioma/*drug therapy/pathology/radiotherapy ; Hematologic Diseases/etiology ; Humans ; Male ; Middle Aged ; Nausea/drug therapy/etiology ; Neoplasm Staging ; Republic of Korea ; Retrospective Studies ; Severity of Illness Index ; Sex Factors ; Vomiting/drug therapy/etiology ; Young Adult

OBJECTIVE: To investigate whether granulocyte-colony stimulating factor (G-CSF) can decrease the extent of ovarian follicle loss caused by cisplatin treatment. METHODS: Twenty-one adult female Sprague-Dawley rats were used. Fourteen rats were administered 2 mg/kg/day cisplatin by intraperitoneal injection twice per week for five weeks (total of 20 mg/kg). Half of the rats (n=7) were treated with 1 mL/kg/day physiological saline, and the other half (n=7) were treated with 100 microg/kg/day G-CSF. The remaining rats (n=7, control group) received no therapy. The animals were then euthanized, and both ovaries were obtained from all animals, fixed in 10% formalin, and stored at 4degrees C for paraffin sectioning. Blood samples were collected by cardiac puncture and stored at -30degrees C for hormone assays. RESULTS: All follicle counts (primordial, primary, secondary, and tertiary) and serum anti-Mullerian hormone levels were significantly increased in the cisplatin+G-CSF group compared to the cisplatin+physiological saline group. CONCLUSION: G-CSF was beneficial in decreasing the severity of follicle loss in an experimental rat model of cisplatin chemotherapy.
Animals ; Anti-Mullerian Hormone/blood ; Antineoplastic Agents/*toxicity ; Biological Markers/blood ; Cisplatin/*toxicity ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Female ; Fertility Preservation/methods ; Granulocyte Colony-Stimulating Factor/*therapeutic use ; Ovarian Follicle/drug effects/pathology ; Primary Ovarian Insufficiency/blood/chemically induced/pathology/*prevention & control ; Rats, Sprague-Dawley

BACKGROUNDZengshengping (ZSP) tablets had inhibitory effects on oral precancerous lesions by reducing the incidence of oral cancer. However, the severe liver toxicity caused by systemic administration of ZSP limits the long-term use of this anti-cancer drug. The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of extracts from ZSP, a Chinese herbal drug, on 7, 12-dimethlbenz(a)anthracene (DMBA) induced oral tumors in hamsters. The study also investigated the anti-cancer mechanisms of the ZSP extracts on oral carcinogenesis.

METHODSDMBA (0.5%) was applied topically to the buccal pouches of Syrian golden hamsters (6 - 8 weeks old) three times per week for six weeks in order to induce the development of oral tumors. Different fractions of ZSP were either applied topically to the oral tumor lesions or fed orally at varying dosages to animals with oral tumors for 18 weeks. Tumor volume was measured by histopathological examination. Tumor cell proliferation was evaluated by counting BrdU labeled cells and by Western blotting for mitogen-activated protein kinase (MAPK) protein levels. The protein levels of apoptosis marker Caspase-3 and regulator Bcl-2 protein were also measured by Western blotting.

RESULTSTopical application of DMBA to the left pouch of hamsters induced oral tumor formation. Animals treated with DMBA showed a loss in body weight while animals treated with ZSP maintained normal body weights. Both the ZSP n-butanol fraction and water fraction significantly reduced tumor volume by 32.6% (P < 0.01) and 22.9% (P < 0.01) respectively. Topical application of ZSP also markedly decreased the BrdU-positive cell numbers in oral tumor lesions and reduced the expression level of MAPK. In addition, ZSP promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production.

CONCLUSIONThe n-butanol and water fractions of ZSP are effective at inhibiting tumor cell proliferation and stimulating apoptosis in oral cancer suggesting that these fractions have chemopreventive effects on DMBA induced oral carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene ; toxicity ; Animals ; Antineoplastic Agents ; therapeutic use ; Cell Transformation, Neoplastic ; drug effects ; Cricetinae ; Drugs, Chinese Herbal ; therapeutic use ; Male ; Mesocricetus ; Mouth Neoplasms ; chemically induced ; drug therapy ; prevention & control

BACKGROUND/AIMS: We retrospectively analyzed comparative toxicities and efficacies of chemotherapy regimens in advanced gastric cancer (AGC) patients who achieved complete response (CR) after chemotherapy. METHODS: We reviewed the medical records of 1,203 patients, who were pathologically diagnosed as AGC in a single center between January 2001 and October 2007. On the basis of the Response Evaluation Criteria in Solid Tumors, CR was evaluated with abdominal computed tomography. Toxicities were evaluated using the National Cancer Institute's common toxicity criteria before each chemotherapy cycle. RESULTS: Among the 1,203 AGC patients enrolled in this study, 568 received chemotherapy and 635 received best supportive care. The major chemotherapy regimens were 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), docetaxel, cisplatin and 5-fluorouracil (DCF) and 5-fluorouracil, leucovorin and irinotecan (FOLFIRI). Among the 568 patients, 51 (9.0%) achieved CR (49 [8.6%] with FOLFOX [n=12], DCF [n=26], or FOLFIRI [n=11] and 2 [0.3%] with etoposide, leucovorin and 5-fluorouracil). For patients administered FOLFOX, DCF, and FOLFIRI, the median time to disease progression was 4 months (range, 1.8-59.5), 15 months (range, 2.9-31.2) and 10 months (range, 2.0-39.5), and the median survival times were 48 months (range, 5.9-74.0), 37 months (range, 14.0-86.0), and 30 months (range, 6.0-50.0), respectively. Grades 3-4 mucositis occurred mostly in patients administered DCF (n=8, 30.8%). Grades 3-4 leucopenia were observed in 1 (8.3%), 11 (42.3%), and 4 (36.4%) patients administered FOLFOX, DCF and FOLFIRI, respectively. No statistically significant differences were observed in the 3 regimens. CONCLUSIONS: All 3 regimens (FOLFOX, DCF and FOLFIRI) were active and tolerable. Their efficacies and toxicities were not significantly different.
Adult ; Aged ; Antineoplastic Agents/*therapeutic use/toxicity ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/toxicity ; Camptothecin/analogs & derivatives/therapeutic use/toxicity ; Cisplatin/therapeutic use/toxicity ; Drug Therapy, Combination ; Female ; Fluorouracil/therapeutic use/toxicity ; Humans ; Leucovorin/therapeutic use/toxicity ; Leukopenia/etiology ; Male ; Middle Aged ; Mucositis/etiology ; Nausea/etiology ; Neoplasm Staging ; Organoplatinum Compounds/therapeutic use/toxicity ; Retrospective Studies ; Stomach Neoplasms/*drug therapy/mortality ; Survival Rate ; Taxoids/therapeutic use/toxicity ; Tomography, X-Ray Computed ; Vomiting/etiology

OBJECTIVETo evaluate the effect of Armillariella tabescens on cisplatin chemotherapy-induced gastrointestinal tract reaction.

METHODSForty-eight male Sprague-Dawley rats were randomized into control group, model group, low dose Armillariella tabescens group, middle dose Armillariella tabescens group, high dose Armillariella tabescens group and ondansetron group. The rats were injected intraperitoneally with cisplatin to induce pica, and observe the effect of Armillariella tabescens on consumption of kaolin, food, water and body weight.

RESULTS24-72 h after cisplatin administration, in the middle dose Armillariella tabescens group, the high dose Armillariella tabescens group and the ondansetron group, the kaolin intake was significantly lower than that in the model group, respectively (P<0.05). The most significant difference was between the high dose Armillariella tabescens group [(0.58 +/- 0.23) g/24 h] and the control group [(2.16 +/- 0.98) g/24 h] at 24 h after cisplatin administration. The variables, such as consumption of food during 48-72 h (P<0.05), water during 48-72 h (P<0.05), and body weight at 72 h (P<0.05) in the middle dose Armillariella tabescens group were significantly higher than those in the model group, but no statistically significant difference between the ondansetron group and the model group (P>0.05).

CONCLUSIONSArmillariella tabescens can effectively inhibit the cisplatin-induced pica response, and the middle dose Armillariella tabescens group is significantly better than the model group in improving the food intake reduction, water intake reduction and body weight loss.

Agaricales ; chemistry ; Animals ; Antiemetics ; therapeutic use ; Antineoplastic Agents ; toxicity ; Biological Therapy ; methods ; Body Weight ; Cisplatin ; toxicity ; Drinking ; Eating ; Kaolin ; Male ; Ondansetron ; therapeutic use ; Pica ; chemically induced ; therapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Long circulating paclitaxel microemulsions (TXL-M) were prepared and its anticancer effect was evaluated in metronomic chemotherapy of cancer using animal tumor models. In TXL-M, paclitaxel was dissolved in vitamin E and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) was used as surfactant. The shape and particle size distribution of TXL-M were evaluated using an electronic microscope and a laser size scanner. The toxicity comparisons of TXL-M and paclitaxel were conducted using mice. Its anticancer effect and long circulation were evaluated using animal tumor model in C57BL/6 mice. The average diameter of TXL-M was (98.6 +/- 11.2) nm and its zeta potential was (-32.4 +/- 6.8) mV. Compared with paclitaxel, TXL-M showed lower toxicity. When used in metronomic chemotherapy of cancer, TXL-M showed longer circulation time in the blood and greater anticancer effect than paclitaxel. Thus, TXL-M is a better candidate for metronomic chemotherapy of cancer than paclitaxel injection.
Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; therapeutic use ; toxicity ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Paclitaxel ; administration & dosage ; therapeutic use ; toxicity ; Tumor Cells, Cultured

We have evaluated the efficacy and safety of the combination of capecitabine and vinorelbine in metastatic breast cancer (MBC) patients previously treated with anthracycline-and taxane-containing regimens. Between April 2000 and September 2002, 44 female MBC patients received oral capecitabine (1,250 mg/m(2) twice daily on days 114), and intravenous vinorelbine (25 mg/m2 on days 1 and 8) during each 3 weekchemotherapy cycle (median, 5 cycles/patient; total, 235 cycles). One patient achieved a complete response and 21 patients had partial responses, giving an overall response rate of 50% in the intention-to-treat analysis (95% CI, 35.0-65.0%). Median duration of response was 6.0 months (range 1.2-23.0 months). Patients were followed- up for a median of 16 months, with median progression-free survival being 5.3 months, and median overall survival being 17 months. Toxicities included grades III and IV neutropenia in 63 (26.8%) and 4 (1.7%) cycles, respectively, and grades II and III hand-foot syndrome in 12 (5.1%) and 4 (1.7%) cycles, respectively. Other nonhematologic toxicities were minimal and manageable. In conclusion, the combination of capecitabine and vinorelbine was effective and well tolerated in MBC patients even after treatment with anthracyclines and taxanes.
Adult ; Aged ; Anthracyclines/*therapeutic use ; Antineoplastic Agents/*therapeutic use/toxicity ; Breast Neoplasms/*drug therapy/*pathology ; Deoxycytidine/*analogs & derivatives/*therapeutic use/toxicity ; Drug Therapy, Combination ; Female ; Humans ; Middle Aged ; Neoplasm Metastasis ; Prodrugs ; Retrospective Studies ; Survival Rate ; Taxoids/*therapeutic use ; Treatment Outcome ; Vinblastine/*analogs & derivatives/*therapeutic use/toxicity