FF-10850, a Novel Liposomal Topotecan Achieves Superior Antitumor Activity via Macrophage- and Ammonia-Mediated Payload Release in the Tumor Microenvironment.

Topotecan, an approved treatment for refractory or recurrent ovarian cancer, has clinical limitations such as rapid clearance and hematologic toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior antitumor activity to topotecan in ovarian cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian cancer patient-derived xenograft model.

In vivo imaging of tissue-remodeling activity involving infiltration of macrophages by a systemically administered protease-activatable probe in colon cancer tissues.

This study evaluated the detection of tumors using in vivo imaging with a commercially available and systemically administered protease-activatable fluorescent probe, ProSense. To this end, we analyzed the delivery and uptake of ProSense as well as the target protease and its cellular source in a mouse xenograft tumor model. In vivo and ex vivo multi wavelength imaging revealed that ProSense signals accumulated within tumors, with preferential distribution in the vascular leakage area that correlates with vasculature development at the tumor periphery.

Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model.

Purpose: Some goitrogens promote thyroid carcinogenesis in rats in an initiation-promotion model; this model frequently produces carcinomas that invade fibrously thickened capsules, termed capsular invasive carcinomas (CICs). The present study tested a hypothesis that CICs originate from parenchymal proliferative lesions located beneath the capsule.

Methods: Cell proliferation activity, cell-cycle kinetics and cellular invasion were immunohistochemically examined in subcapsular proliferative lesions in male F344 rats treated with an anti-thyroid agent, propylthiouracil or sulfadimethoxine, during the tumor-promotion phase after initiation with N-bis(2-hydroxypropyl)nitrosamine.

Protective Effect of Stachybotrys microspora Triprenyl Phenol-7on the Deposition of IgA to the Glomerular Mesangium in Nivalenol-induced IgA Nephropathy Using BALB/c Mice.

Activators of tissue proteolysis including Stachybotrys microspora triprenyl phenol (SMTP)-7 are a new class of agents that are expected to be effective for amelioration of chronic tissue destructive diseases. The present study was performed to examine whether SMTP-7 is effective for the amelioration or protection of early-stage IgA nephropathy (IgAN) induced by nivalenol (NIV) in female BALB/c mice. In Experiment 1, mice were administered NIV at 24 ppm in diet for 8 weeks, and during the NIV treatment, they were intraperitoneally injected with SMTP-7 (10 mg/kg) three times a week.

Lac color inhibits development of rat thyroid carcinomas through targeting activation of plasma hyaluronan-binding protein.

Coccid-derived natural food colorants contain active ingredients that potentiate inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In the present study, we examined the effect of lac color (LC) and cochineal extract (CE), representative coccid-derived colorants containing laccaic acid and carminic acid as active ingredients, in an intracapsular invasion model of experimental thyroid cancers using rats. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSIc rats were fed a powdered diet containing 5.

Promoting effects of carminic acid-enriched cochineal extracts on capsular invasive thyroid carcinomas through targeting activation of angiogenesis in rats.

Cochineal extracts (CE) is a coccid-derived natural food colorant containing carminic acid (CA) as an active ingredient that potentiates inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In our previous study, dietary administered CE (CA: 28.5% in CE) has shown to promote the macroscopic development of capsular invasive carcinomas (CICs) associated with up-regulation of angiogenesis-related genes in an intracapsular invasion model of experimental thyroid cancers using rats.

Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine.

The liver tumor-promoting effects of indole-3-carbinol (I3C), a cytochrome P450 (CYP) 1A inducer found in cruciferous vegetables, were investigated using a medium-term hepatocarcinogenesis model in rats. Six-week-old male F344 rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing 0 (DEN-alone), 0.25, 0.

Preventive effects of calcitriol on the development of capsular invasive carcinomas in a rat two-stage thyroid carcinogenesis model.

We have shown phosphoinositide 3-kinase (PI3K)/Akt signaling activation in thyroid capsular invasive carcinomas (CICs), which are highly induced by promotion with sulfadimethoxine (SDM) in a rat 2-stage thyroid carcinogenesis model. To examine the potency of calcitriol, a synthetic vitamin D3 analog, on the development or progression of CICs, male F344 rats were injected with calcitriol (0.1 µg/kg body weight) three times a week intraperitoneally, during an entire period of SDM-promotion for 13 weeks (Experiment 1) or during the last 2 weeks of a 15-week SDM-promotion (Experiment 2).

Relationship between CYP1A induction by indole-3-carbinol or flutamide and liver tumor-promoting potential in rats.

To investigate liver tumor-promoting potentials of indole-3-carbinol (I3C) and flutamide (FLU), changes in mRNA expression of Cyp1a and genes encoding antioxidant/detoxifying enzymes in the liver, 6-week-old male F344 rats were subjected to medium-term liver bioassay. β-Naphthoflavone (BNF), a strong CYP1A inducer, was also used for comparison. Two weeks after initiation with N-diethylnitrosamine (DEN), animals were fed a basal diet (untreated controls) or a diet containing 0.

Involvement of PTEN/Akt signaling in capsular invasive carcinomas developed in a rat two-stage thyroid carcinogenesis model after promotion with sulfadimethoxine.

Purpose: Rat thyroid follicular cell carcinomas invading into the thyroid capsule are highly produced by promotion with sulfadimethoxine (SDM) in a rat two-stage thyroid carcinogenesis model. In this study, we investigated the participation of phosphoinositide 3-kinase (PI3K) signaling pathway that is associated with malignant phenotypes of many cancers on the development of SDM-induced capsular invasive carcinomas.

Methods: Thyroid proliferative lesions developed 10 or 15 weeks after promotion with SDM in male F344 rats initiated with N-bis(2-hydroxypropyl)nitrosamine were immunohistochemically analyzed with regard to cellular distribution of phosphatase and tensin homolog (PTEN) and Akt isoforms, as well as their downstream molecules.

Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model.

To clarify the involvement of signaling of transforming growth factor (TGF)-β during the hepatocarcinogenesis, the immunohistochemical distribution of related molecules was analyzed in relation with liver cell lesions expressing glutathione S-transferase placental form (GST-P) during liver tumor promotion by fenbendazole, phenobarbital, piperonyl butoxide, or thioacetamide, using rats. Our study focused on early-stage promotion (6weeks after starting promotion) and late-stage promotion (57weeks after starting promotion). With regard to Smad-dependent signaling, cytoplasmic accumulation of phosphorylated Smad (phospho-Smad)-2/3 - identified as Smad3 by later immunoblot analysis - increased in the subpopulation of GST-P(+) foci, while Smad4, a nuclear transporter of Smad2/3, decreased during early-stage promotion.

Sustained production of Reelin-expressing interneurons in the hippocampal dentate hilus after developmental exposure to anti-thyroid agents in rats.

To detect molecular evidence reflecting a permanent disruption of neuronal development due to hypothyroidism, distribution of Reelin-producing cells that function in neuronal migration and positioning was analyzed in the hippocampal dentate hilus using rats. From gestation day 10, maternal rats were administered either 6-propyl-2-thiouracil (PTU) at 3 or 12ppm (0.57 or 1.

Tumor promotion by copper-overloading and its enhancement by excess iron accumulation involving oxidative stress responses in the early stage of a rat two-stage hepatocarcinogenesis model.

To investigate liver tumor promotion mechanisms of copper (Cu)- and iron (Fe)-overloading, immunolocalization of metal-related biomolecules and lipid peroxidation end products was examined in preneoplastic liver cell foci that expressed glutathione S-transferase placental form (GST-P) in early-stage tumor promotion over 6 weeks in a rat two-stage hepatocarcinogenesis model. Gene expression and concentrations of thiobarbituric acid-reactive substance (TBARS) in the liver were also analyzed. Cu-overloading alone exerted a weak promoting activity, which was enhanced by Fe-overloading.

The threshold dose for liver tumor promoting effects of dicyclanil in ICR mice.

To determine the threshold dose of dicyclanil (DC) that induces hepatocellular tumor-promoting effects associated with reactive oxygen species (ROS) generation via their metabolic pathways, partial hepatectomized ICR male mice were fed diets containing 0, 187.5, 375 or 750 ppm DC after an intraperitoneal injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Immunohistochemically, the proliferating cell nuclear antigen (PCNA)-positive cell ratio was significantly increased in the DEN + 750 ppm DC group compared with the DEN alone group.

Elevation of cell proliferation via generation of reactive oxygen species by piperonyl butoxide contributes to its liver tumor-promoting effects in mice.

Piperonyl butoxide (PBO) is a pesticide synergist used with pyrethroids as a domestic insecticide, and it acts as a non-genotoxic hepatocarcinogen in rats and mice. To clarify whether oxidative stress is involved in the liver tumor-promoting effect of PBO in mice, male mice were subjected to two-thirds partial hepatectomy, followed by N-diethylnitrosamine (DEN) treatment, and given a diet containing 0.6% PBO for 25 weeks.

Induction of GST-P-positive proliferative lesions facilitating lipid peroxidation with possible involvement of transferrin receptor up-regulation and ceruloplasmin down-regulation from the early stage of liver tumor promotion in rats.

To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis.

Cytokeratin 8/18 is a useful immunohistochemical marker for hepatocellular proliferative lesions in mice.

In order to clarify whether cytokeratin (CK) 8/18 is a useful immunohistochemical marker for hepatocellular proliferative lesions in mice, partially hepatectomized male ICR mice were given 0.6% piperonyl butoxide (PBO) for 8 (Experiment I) or 25 weeks (Experiment II) after N-diethylnitrosamine (DEN) initiation treatment, and the livers were subjected to histological examinations on hematoxylin and eosin (HE) stained sections, CK8/18 immunohistochemistry and gamma-glutamyl transpeptidase (GGT) histochemistry. In Experiment I, the multiplicity of hepatocellular foci in paraffin-embedded sections which were observed in HE-stained sections and positive for CK8/18 was 10.

Antioxidant enzymatically modified isoquercitrin or melatonin supplementation reduces oxidative stress-mediated hepatocellular tumor promotion of oxfendazole in rats.

To clarify whether enzymatically modified isoquercitrin (EMIQ) or melatonin (MLT) supplementation reduces oxidative stress-mediated hepatocellular tumor-promoting effect of oxfendazole (OX), a benzimidazole anthelmintic, male rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing OX (500 ppm) for 10 weeks with or without EMIQ (2,000 ppm) or MLT (100 ppm) in the drinking water after DEN initiation. One week after the commencement of the administration of OX, rats were subjected to two-thirds of partial hepatectomy. The number of GST-P-positive foci promoted by OX was significantly inhibited by the combined antioxidant EMIQ or MLT administration, and the area of GST-P-positive foci was inhibited by the administration of MLT.

No Modifying Effect of Antioxidant N-Acetyl-L-Cysteine on Fenofibrate-induced Hepatocarcinogenesis in Rats.

To clarify the modifying effect of N-Acetyl-L-Cysteine (NAC), which has antioxidative ability, on hepatocarcinogenesis promoted by fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR) alpha agonist , male F344/N rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiator followed by administration of a diet containing 3,000 ppm of FF for 16 weeks. Two-thirds partial hepatectomy was performed 1 week after the FF treatment. Additionally, NAC treatments for 14 weeks from 2 weeks after the FF treatment were performed.

Rapid deposition of glomerular IgA in BALB/c mice by nivalenol and its modifying effect on high IgA strain (HIGA) mice.

To clarify the underlying mechanisms of IgA nephropathy (IgAN) induced by nivalenol (NIV), a trichothecene mycotoxin, we examined the time and dose relationships of glomerular deposition of IgA by NIV in BALB/c mice (Experiment 1), and also evaluated the modification of NIV on spontaneous IgAN in an inbred murine model, a high IgA strain (HIGA), during its early stage of pathogenesis (Experiment 2). In Experiment 1, female BALB/c mice were given a diet containing 0, 12, or 24 ppm concentration of NIV for 4 or 8 weeks. An increase in serum IgA levels was found at 24 ppm from 4 weeks.

Induction of liver preneoplastic foci in F344 rats subjected to 28-day oral administration of diheptyl phthalate and its in vivo genotoxic potential.

To investigate possible potential inducing preneoplastic lesions in liver and in vivo genotoxic potential of diheptyl phthalate (DHP), male F344 rats were subjected to repeated oral administration of DHP at 0, 2.5 or 5 g/kg/day for 28 days. In addition, F344 rats were subjected to once or 14 repeated oral administrations of 5 g/kg/day of DHP, and their livers were subjected to analysis in an alkaline single-cell gel electrophoresis (comet) assay.

Involvement of glycogen synthase kinase-3beta signaling and aberrant nucleocytoplasmic localization of retinoblastoma protein in tumor promotion in a rat two-stage thyroid carcinogenesis model.

To investigate the cell cycle kinetics during the tumor promotion process induced by hypothyroidism in a rat model of thyroid follicular cell carcinogenesis, immunohistochemical analysis of cell cycle molecules and related signaling molecules was performed in conjunction with analysis of cell proliferation activity in an initiation-promotion model. Male F344 rats were injected with N-bis(2-hydroxypropyl)nitrosamine, and one week later treated with 6-propyl-2-thiouracil (PTU) at 12ppm in the drinking water for 4, 10 or 15 weeks. At each time point, proliferative lesions increased the expression of cyclin A, cyclin D, cyclin E and cyclin-dependent kinase (Cdk)-2, in association with the development of lesion stages from the early focal hyperplasia to the late carcinoma, while a subpopulation of proliferative lesions showed decreased numbers of both cell division cycle-2- and Ki-67-positive cells at week 15 compared with that at week 10, suggesting a reduced promoting effect of serum thyroid-stimulating hormone in the sensitive cellular population after long-term exposure to PTU.