RESUMO
Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML.
Assuntos
Leucemia Mieloide Aguda , Quinolonas , Humanos , Animais , Camundongos , Quinolonas/uso terapêutico , Sinergismo Farmacológico , Leucemia Mieloide Aguda/metabolismo , Daunorrubicina/farmacologia , Daunorrubicina/uso terapêutico , Citarabina/farmacologia , Citarabina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (Japanese: Reishi or Mannentake) (designated as MAK) exerted a protective effect against induction of aberrant crypt foci (ACF) by azoxymethane (AOM) and small-intestinal damage induced by the anticancer drug 5-FU. Six-week-old male F344 rats were fed a basic diet (MF), either alone or containing 2.5 % MAK, beginning 1 week before treatment with AOM. The rats were then given subcutaneous injections of AOM (15 mg/kg body weight) once in a week for 3 weeks. Next, beginning 1 day after the final AOM treatment, 25 or 80 mg/kg 5-FU was injected intraperitoneally three times at 5-day intervals. Finally, the rats were killed 3.5 days after the last injection of 5-FU. The large and small intestines were removed, and tissue specimens were examined for both ACF in the large intestine and regeneration of small-intestinal crypts. The number of ACF was significantly decreased by treatment with 25 mg 5-FU and further decreased by 25 mg 5-FU + MAK in comparison with 5-FU alone. Moreover, there was a greater degree of recovery from small-intestinal damage in the 5-FU + MAK groups than in rats that had received 5-FU alone. The present results indicate that MAK ameliorates the colon precancerous lesions induced by AOM and the small-intestinal injury caused by 5-FU, suggesting that MAK could have potential as a preventive agent against colonic precancer, which is a common adverse effect of chemotherapy.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Meios de Cultura/farmacologia , Fluoruracila/administração & dosagem , Intestino Delgado/efeitos dos fármacos , Reishi/química , Focos de Criptas Aberrantes , Animais , Azoximetano/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Meios de Cultura/química , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/lesões , Intestino Delgado/lesões , Masculino , Micélio/química , Ratos , Ratos Endogâmicos F344 , Água/químicaRESUMO
The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum (Reishi) mycelia (MAK) is able to protect the small intestine against damage induced by anti-cancer drugs. Six-week-old male B6C3F1/Crlj mice were fed a basal diet (MF) alone or with various doses of MAK or Agarics blazei Murrill (AGA) beginning one week before treatment with the anti-cancer drugs. Mice were sacrificed 3.5 days after injection of the anti-cancer drug, the small intestine was removed and tissue specimens were examined for the regeneration of small intestinal crypts. In experiment 1, the number of regenerative crypts after the administration of 5-fluorouracil (5FU) intravenously (250 mg/kg) or intraperitoneally (250 or 500 mg/kg) was compared after treatment with MAK or AGA. MAK protected against 5FU-induced small intestinal injury whereas AGA did not. In experiment 2, we investigated the protective effect of MAK against small intestinal injury induced by the anti-cancer drugs: UFT (tegafur with uracil; 1,000 mg/kg, orally), cisplatin (CDDP; 12.5 and 25 mg/kg, intraperitoneally), cyclophosphamide (CPA; 250 mg/kg, orally) and gefitinib (Iressa; 2,000 and 4,000 mg/kg, orally). UFT and CDDP decreased the number of regenerative crypts, but treatment with MAK attenuated the extent of UFT- or CDDP-induced small intestinal injury. CPA or Iressa plus MAK up-regulated crypt regeneration. The present results indicate that MAK ameliorates the small intestinal injury caused by several anti-cancer drugs, suggesting that MAK is a potential preventive agent against this common adverse effect of chemotherapy.
RESUMO
This study was undertaken to investigate induction of tumors by monoenergetic neutrons in B6C3F1 mice. Individual groups of 6 week-old animals of both sexes (about 30 mice/group) were exposed to 0.5 Gy of various monoenergetic neutrons (dose rate 0.5 cGy/min) and then observed for 13 months. The incidences of tumors (mainly liver neoplasms) in non-irradiated male and female controls were 11% and 0%, respectively. In the irradiated animals, the incidences were 53%, 50%, 60% and 43% in males, and 75%, 81%, 71%, and 85% in females, after 0.18, 0.32, 0.6 and 1.0 MeV neutron exposure, respectively. There were no significant differences in the tumor induction rate among the different energy groups.
Assuntos
Modelos Animais de Doenças , Neoplasias Hepáticas/patologia , Neoplasias Induzidas por Radiação/patologia , Nêutrons , Animais , Relação Dose-Resposta à Radiação , Exposição Ambiental , Feminino , Masculino , Camundongos , Nêutrons/classificação , Doses de RadiaçãoRESUMO
While organ-specific stem cells with roles in tissue injury repair have been documented, their pathogenic significance in diseases and the factors potentially responsible for their activation remain largely unclear. In the present study, heart, kidney, brain, and skin samples from F344 transgenic rats carrying the GFP gene were transplanted into normal F344 rat liver one day after an intraperitoneal injection (i.p.) of carbon tetrachloride (CCl(4)) to test their differentiation capacity. The transplantation was carried out by female donors to male recipients, and vice versa. One week after transplantation, GFP antigen-positive cells with phenotypic characteristics of hepatocytes were noted. After two weeks, their extent increased, and at 4 weeks, large areas of strongly GFP-stained cells developed. All recipient livers had GFP antigen-positive hepatocyte cells. PCR analysis coupled with laser capture micro-dissection (LCM) revealed those cells to contain GFP DNA. Thus, our results indicate that tissue stem cells have multipotential ability, differentiating into hepatocytes when transplanted into an injured liver.
Assuntos
Transplante de Tecido Encefálico/fisiologia , Diferenciação Celular/fisiologia , Transplante de Coração/fisiologia , Transplante de Rim/fisiologia , Fígado/fisiologia , Transplante de Pele/fisiologia , Transplante Heterotópico , Células-Tronco Adultas/transplante , Animais , Animais Geneticamente Modificados , Intoxicação por Tetracloreto de Carbono/fisiopatologia , Proliferação de Células , Feminino , Proteínas de Fluorescência Verde/genética , Regeneração Hepática/fisiologia , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
A water-soluble extract from the culture medium of Ganoderma lucidum (Rei-shi) mycelia (MAK) has been shown to exert a potent chemopreventive effect. The present study was designed to investigate the effects of dietary MAK supplementation on the development of lung tumors initiated by N-nitrosobis (2-hydroxypropyl) amine (BHP) in male Slc:Wistar rats. A total of 77 animals, 6 weeks of age, were divided into 5 groups and given BHP (2,000 ppm) in their drinking water for 10 weeks. The normal controls were not supplied with BHP. After treatment with the carcinogen, the rats were fed a normal control MF solid diet, or the same diet containing MAK (1.25%, 2.5% or 5%) for 12 weeks. Macroscopically, all the doses of MAK reduced the number of nodules, and the effect of 5% MAK was found to be especially significant. Microscopically, an increase in the number of proliferating cell nuclear antigen (PCNA)-negative tumors and a decrease in the number of tumors strongly positive for PCNA were observed in the tissue sections from the rats that had received all the doses of MAK. The present results thus indicate that dietary supplementation with MAK inhibits the development of lung tumors, suggesting that MAK may be a potent chemopreventive agent against lung carcinogenesis.
Assuntos
Adenocarcinoma/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Micélio/química , Reishi/química , Adenocarcinoma/induzido quimicamente , Animais , Carcinógenos/toxicidade , Meios de Cultura/química , Dieta , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Neoplasias Pulmonares/induzido quimicamente , Masculino , Nitrosaminas/toxicidade , Antígeno Nuclear de Célula em Proliferação/biossíntese , Antígeno Nuclear de Célula em Proliferação/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
A unique garlic preparation, aged garlic extract (AGE), was examined for its modifying effect on diethylnitrosamine (DEN)-induced neoplasia of the liver in male F344 rats, using the medium-term bioassay system based on the 2-step model of hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of induced glutathione S-transferase placental form (GST-P)-positive hepatocellular foci. GST-P-positive foci were significantly decreased in rats treated with AGE at doses of 2, 5, and 10 mL/kg, i.g., 5 times per week during the promotion phase. In addition, to clarify the mechanism underlying the inhibitory effect of AGE, the effect of AGE on hepatocellular proliferation was evaluated using partially hepatectomized rats as a liver-regeneration model. The bromodeoxyuridine-labeling indices in the livers of the AGE group were significantly lower than those in the control group at 24 h, the maximum proliferation period after partial hepatectomy. These findings indicate that AGE inhibited the development of putative preneoplastic lesions in rat hepatocarcinogenesis, involving a slowing in the proliferation rate of liver cells after partial hepatectomy.
Assuntos
Alho , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Lesões Pré-Cancerosas/prevenção & controle , Animais , Peso Corporal , Bromodesoxiuridina , Carcinógenos , Dimetilidrazinas , Comportamento Alimentar , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Índice Mitótico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Endogâmicos F344RESUMO
The present study was designed to investigate the effects of fermented miso (fermented soybean paste) on the induction of colon tumors by azoxymethane (AOM) in male F344 rats. A total of 91 rats, 6 weeks of age, were divided into 5 groups and given weekly subcutaneous injections of AOM (15 mg/kg body wt) for 3 weeks. The animals were placed on diets one week before the first AOM dose: commercial normal control MF diet or a diet containing 10% 2-year, 180-day fermented, or 3-4-day fermented miso. There were no differences in body and organ weights, and no aberrant crypt foci (ACF) among carcinogen-treated groups at week 25. The rates of tumor incidence were 45%, 85%, 75% and 60% with the 2-year, 180-day, and 3-4-day fermented miso and MF, respectively, and those for colon tumors were 34%, 55%, 60% and 55%, respectively. The size of well-differentiated adenocarcinomas and total (well differentiated and signet ring cell) adenocarcinomas in the 180-day fermented miso group was significantly smaller than that in the 2-year fermented miso and MF+AOM groups. Nuclear staining of beta-catenin in colon tumors was increased for the 3-4-day fermented miso compared to the 180-day fermented miso. Cdx2 staining tendency was decreased in colon tumors and adenocarcinomas compared to normal mucosa and ACF, which stained in 100% of cases. In addition, the PCNA index was significantly reduced in the 180-day group compared with those groups receiving the 3-4-day fermented miso and MF diet. The germinal region was also decreased. The present results indicate that dietary supplementation with 180-day fermented dietary miso could act as a chemopreventive agent for colon carcinogenesis.