No abstract

Sol‐gel‐processed sintered silica xerogel was studied as a controllable, dissolvable, implantable material. The erosion of the matrix and the release of the preadsorbed drug toremifene citrate was investigated both in vitro and in vivo using mice. In an in vitro dissolution study, 50 to 60% of the drug was released after 24 h, according to the square root of time kinetics, and the weight loss of the silica was 24 wt %. Silica xerogel with tritium‐labeled toremifene was implanted subcutaneously in mice for 56 days. To determine the amount of tritiated drug remaining in the silica disks at the implantation site, the disks were excised periodically and the radioactivity measured. About 40% of the radioactivity was released during the first 4 days and all of it within 28 days. Radioactivity also was measured in the liver, lungs, kidneys, uterus, and blood. The radioactivity reached a maximum level after 4 days in the liver, kidneys, and lungs and slowly decreased until all of the drug had been released from the matrix after 28 days. After release of the drug (28 days) the amount of remaining silica xerogel implant was 45 wt %, and at the end of the study (56 days) it was 24 wt %. In the histopathological study, sintered silica xerogel did not show any tissue toxicity at the site of the implantation, in the liver, or in the kidneys. It was concluded that sintered silica xerogel is a biocompatible and controllably resorbable material and therefore is a promising matrix for use in the sustained delivery of drugs. © 1999 John Wiley & Sons, Inc. J Biomed Mater Res, 44, 162–167, 1999.

The hepatoproliferative and cytochrome P450 enzyme inducing effects of two antiestrogens, tamoxifen and toremifene, were compared in female Sprague-Dawley rats using immunohistochemical staining methods. Equimolar doses of the antiestrogens (tamoxifen 45 mg/kg and toremifene 48 mg/kg) were given by oral administration to 6-week-old rats for 12 months including a 3-month recovery period. Controls received the vehicle carboxymethylcellulose. Altogether 90 rats were used in the study. Five rats per dose group were killed after 14 days, 5 weeks, 3, 6 and 12 months of treatment as well as after the 3-month recovery period. Hepatocellular carcinoma was found in four out of five rats after 12 months of tamoxifen treatment. After the 3-month recovery period all tamoxifen-treated rats had large liver tumors (diameter up to 3 cm). No tumors were observed in toremifene-treated rats. Liver cell proliferation was measured by the index of proliferating cell nuclear antigen (PCNA) expression. Immunohistochemical staining with the placental form of glutathione S-transferase (GST-P) was used as a marker for preneoplastic foci. Cytochrome P450 induction was measured using specific antibodies to isoenzymes. Tamoxifen increased the incidence of GST-P-positive foci significantly by 3 months of treatment but toremifene did not as compared with the controls. Liver cell proliferation increased significantly only in the liver tumors of tamoxifen-treated rats after 12 months of treatment and during the recovery period. Both antiestrogens induced the isoenzymes CYP2B1/2 and CYP3A1 within 14 days although tamoxifen was a more powerful inducer. Immunohistochemistry of rat liver sections showed a centrilobular localization of these induced enzyme proteins. The expression of CYP2B1/2 and 3A1 could also be observed in foci after 3 and 6 months of administration and in liver adenomas and in some carcinomas after 12 months of administration with tamoxifen. The results show that tamoxifen, but not toremifene, has the potential to induce and promote the development of rat hepatocarcinogenesis in this experimental model.

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC 50 6-35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC 50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC 50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.

The carcinogenic potential of the nonsteroidal triphenylethylene antiestrogen toremifene (Fareston) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 and 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study weeks 1-16) or once every four weeks thereafter (study weeks 17-104). Blood samples were taken at weeks 34, 52 and 104 and the plasma concentrations of toremifene, as well as the two main metabolites (deaminohydroxy)toremifene and N-demethyltoremifene, were measured. All doses of toremifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced incidences of pituitary tumors. This was evident in all dose groups. Drug-related decrease of mammary tumors in females (at all doses) and testicular tumors in male rats (doses > or = 1.2 mg/kg/day) were also evident. The incidence of the preneoplastic foci of basophilic hepatocytes were significantly decreased in treated female groups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-related changes were observed in the genital organs, thyroid, spleen, mammary gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or reduced incidences of pituitary, mammary or testicular tumors. This study indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.