betadex and Kidney-Neoplasms

Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles-PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC).. We produced a novel cationic polymer-PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro.. We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo.. HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; beta-Cyclodextrins; Carcinoma, Renal Cell; Cell Cycle; Cell Movement; Cell Proliferation; Drug Synergism; Female; Folic Acid; Hepatocyte Growth Factor; Humans; Kidney Neoplasms; Kringles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplastic Stem Cells; Polyethylene Glycols; Polyethyleneimine; Sorafenib; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or beta-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by beta-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.

Topics: Adenoma, Chromophobe; Animals; beta-Cyclodextrins; Carcinogens; Cocarcinogenesis; Cyclodextrins; Cystadenoma; Female; Gentamicins; Kidney Neoplasms; Nephrectomy; Rats; Rats, Wistar; Stilbenes

A monoclonal antibody, NR-2 MAb, against one of the rat renal cell tumor-associated antigens was developed. NR-2 MAb belonged to IgM class and recognized a polypeptide of 81,000 daltons designated as NR-2 antigen, which is of non-glycoprotein nature with a pI of 4.6. NR-2 MAb was employed to probe the histogenesis of renal cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine followed by trisodium nitrilotriacetate monohydrate. Immunohistochemical analysis indicated that NR-2 antigen was expressed in simple hyperplasia, adenomatous hyperplasia and renal cell tumors. Both clear cells and basophilic cells of the simple hyperplasia showed equally strong positive reactions with NR-2 MAb, whereas the vacuolated epithelium was negative. Furthermore, the proximal tubules in nontumorous areas also expressed NR-2 antigen, suggesting that the hyperplastic lesions which eventually lead to renal cell tumors may derive from epithelia of proximal tubules and not directly from vacuolated epithelium. Such NR-2 antigen-positive epithelia of proximal tubules seem to be initiated cells. NR-2 MAb also cross-reacted with preneoplastic liver lesions.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; beta-Cyclodextrins; Biomarkers, Tumor; Carcinoma, Renal Cell; Cyclodextrins; Hyperplasia; Kidney Neoplasms; Liver; Male; Molecular Weight; Neoplasm Proteins; Rats; Rats, Inbred Strains

1,2-Dichlorovinylcysteine (DCVC) is known to cause enlarged nuclei in renal proximal tubule epithelium. This study further characterized the cellular changes induced by DCVC. Also a preliminary investigation of the initiator and promoter potential of DCVC was conducted. When given for 4 weeks in drinking water to Swiss-Webster mice, DCVC (50 or 100 micrograms/ml) caused a progressive change in renal epithelia which was persistent at 23 weeks. Enlarged nuclei with uneven chromatin dispersal, multiple nucleoli, and irregular nuclear membranes resided in enlarged, abnormally-shaped cells. These changes were resolved by week 50. Mice initiated with dimethylnitrosamine developed renal tumors by week 27. Mice fed DCVC (10 or 50 micrograms/ml) for 14 weeks following dimethylnitrosamine initiation, had a slightly higher tumor incidence, a higher incidence of invasive tumors, and had multiple renal tumors unlike animals given dimethylnitrosamine alone.

Topics: Animals; beta-Cyclodextrins; Cocarcinogenesis; Cyclodextrins; Cysteine; Dimethylnitrosamine; Drug Synergism; Kidney; Kidney Neoplasms; Mice

Injection (sc) of beta-cyclodextrin (beta-C) increased the number and size of renal tubular cell tumors in inbred Wistar (W) rats treated with 1,000 ppm of N-ethyl-N-hydroxyethylnitrosamine (EHEN). The incidence of renal tumors at the end of the 32-week experiment was 50% in rats treated with 1,000 ppm EHEN for 2 weeks and 100% in rats treated with 1,000 ppm EHEN for 2 weeks and then given daily sc injections of beta-C for 1 week. The incidence of renal tumors more than 3 mm in diameter was 70% in rats treated with 1,000 ppm EHEN before beta-C but 0% in rats treated with EHEN alone. In addition, beta-C promoted the development of renal tumors in rats treated with 500 ppm EHEN, which is a subthreshold dose for renal tubular cell tumorigenesis. These results show that beta-C promotes EHEN-induced renal tubular cell tumorigenesis.

Topics: Animals; beta-Cyclodextrins; Body Weight; Carcinogens; Cocarcinogenesis; Cyclodextrins; Dextrins; Diet; Diethylnitrosamine; Kidney Cortex; Kidney Neoplasms; Kidney Tubules; Male; Nitrosamines; Organ Size; Rats; Rats, Inbred Strains; Starch