o-(chloroacetylcarbamoyl)fumagillol and Ovarian-Neoplasms

In ovarian cancer patients, the duration of complete response after successful cancer chemotherapy is often short-lived. During that time period, patients usually receive no further maintenance therapy. Ovarian cancer patients in complete remission, however, often begin to show steady increases in their plasma levels of cancer antigen CA-125, 4-6 months before the recurrence of clinical symptoms. For these individuals, we are proposing the administration of angiogenesis inhibitors as a maintenance therapy. Although, in ovarian cancer, CA-125 provides a unique opportunity in identifying those patients requiring further treatment, this concept could be applied to other forms of cancer as other prognostic indicators become available.

Topics: Antineoplastic Agents; CA-125 Antigen; Cyclohexanes; Female; Humans; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; Prognosis; Sesquiterpenes

Good biocompatibility, specific tumor targeting, effective drug loading capacity and persistence in the circulation in vivo are imperative prerequisites for the antitumor efficiency of nanoparticles and their further clinical application. In this study, APRPG (Ala-Pro-Arg-Pro-Gly) peptide-modified poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) nanoparticles (NP-APRPG) encapsulating inhibitors of angiogenesis (TNP-470) (TNP-470-NP-APRPG) were fabricated. TNP-470-NP-APRPG was designed to feature maleimide-PEG-PLA and mPEG-PLA as carrier materials, the APRPG peptide for targeting angiogenesis, PEG for prolonging circulation in vivo and PLA for loading TNP-470. TNP-470-NP-APRPG was confirmed to be approximately 130 nm in size with negative ζ-potential (-14.3 mV), narrow distribution (PDI = 0.27) and spherical morphology according to dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. In addition, X-ray photoelectron spectra (XPS) analyses confirmed 7.73% APRPG grafting on the TNP-470-NP. In vitro, TNP-470-NP-APRPG exhibited effective inhibition of proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Similar findings were observed for the retardation of tumor growth in SKOV3 ovarian cancer-bearing mice, suggesting the significant inhibition of angiogenesis and antitumor efficiency of TNP-470-NP-APRPG. Moreover, no obvious toxic drug responses were observed. Further evidence obtained from the immunohistochemical examination demonstrated that the tumor growth inhibition was closely correlated with the high rate of apoptosis among endothelial cells and the effective blockade of endothelial cell proliferation. These results demonstrate that NP-APRPG is a promising carrier for delivering TNP-470 to treat ovarian cancer and that this approach has the potential to achieve broad tumor coverage in the clinic.

Topics: Angiogenesis Inhibitors; Animals; Cyclohexanes; Drug Delivery Systems; Female; Human Umbilical Vein Endothelial Cells; Humans; Lactic Acid; Mice; Nanoparticles; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Oligopeptides; Ovarian Neoplasms; Ovary; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sesquiterpenes

To elucidate the efficacy of TNP-470 on ovarian carcinomas by using cis-diamminedichloroplatinum (CDDP)-resistant cell lines.. The susceptibility of human ovarian carcinoma-derived cell lines and its resistant cell lines against cis-diamminedichloroplatinum (CDDP) to angiogenesis inhibitor, TNP-470, were analyzed using three human cultured cell lines derived from ovarian carcinoma (TYK, KF-92, and Nakajima) and each CDDP-resistant cell line (TYK-R, TYK-R', KF/ra, KF/rb, Nakajima-S1, and Nakajima-S2).. TNP-470 revealed suppression of thymidine incorporation by all of the nine cell lines linearly dependent on the concentration of TNP-470. Significant suppression was not observed for either uridine or leucine incorporation by all nine cell lines. To elucidate the site of each cell line, in which TNP-470 revealed the antitumor effect, the incorporation of (3)H-TNP-470 by cultured cells or by DNA extracted from cultured cells was examined in the cell lines, and the ratio of (3)H-TNP-470 incorporation by DNA to (3)H-TNP-470 incorporation by cultured cells ranged from 2.3% to 4.4% in three parent cell lines. The ratio in the CDDP-resistant cell lines ranged from 11.0% to 46.7%. The ability of TNP-470 to inhibit neoplastic growth in vivo was evaluated using KF-92, KF/ra, KF/rb, Nakajima, Nakajima-S1, and Nakajima-S2. Concerning KF-92, KF/ra, and KF/rb, 30 mg/kg of TNP-470 significantly suppressed the tumorigenicity of KF-92, 10 and 30 mg/kg of TNP-470 suppressed the tumorigenicity of KF/ra, and 30 mg/kg of TNP-470 suppressed the tumorigenicity of KF/rb. Concerning Nakajima, Nakajima-S1, and Nakajima-S2, TNP-470 revealed no inhibitory effect on the tumorigenicity of Nakajima. Contrary, significant inhibition was observed when 30 mg/kg of TNP-470 was used to the CDDP-resistant cell lines Nakajima-S1 and Nakajima-S2.. These results suggest that the clinical application of TNP-470 may be one of the possible treatments for the CDDP-resistant ovarian carcinomas.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Endometrioid; Cell Division; Cell Line, Tumor; Cisplatin; Cyclohexanes; Cystadenocarcinoma, Serous; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Nude; Neoplasm Proteins; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; RNA, Neoplasm; Sesquiterpenes; Xenograft Model Antitumor Assays

In an era when molecular and targeted anticancer therapeutics is a major focus and when understanding drug dynamics in tumor is critical, it seems advantageous to be able to relate drug concentrations in tumors to corresponding biological end points. To that end, a novel method, based on physiologically based hybrid pharmacokinetic models, is presented to predict human tumor drug concentrations. Such models consist of a forcing function, describing the plasma drug concentration-time profile, which is linked to a model describing drug disposition in tumors. The hybrid models are originally derived from preclinical data and then scaled to humans. Integral to the scale-up procedure is the ability to derive human forcing functions directly from clinical pharmacokinetic data. Three examples of this approach are presented based on preclinical investigations with carboplatin, topotecan, and temozolomide. Translation of these preclinical hybrid models to humans used a Monte Carlo simulation technique that accounted for intrasubject and intersubject variability. Different pharmacokinetic end points, such as the AUC tumor, were extracted from the simulated human tumor drug concentrations to show how the predicted drug concentrations might be used to select drug-dosing regimens. It is believed that this modeling strategy can be used as an aid in the drug development process by providing key insights into drug disposition in tumors and by offering a foundation to optimize drug regimen design.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Computer Simulation; Cyclohexanes; Dacarbazine; Female; Humans; Male; Models, Biological; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; Predictive Value of Tests; Rats; Rats, Inbred F344; Rats, Nude; Sesquiterpenes; Temozolomide; Topotecan; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

To study the effect of an angiogenesis inhibitor TNP-470 (TNP) used alone and in combination with cytoxan (CTX) in the treatment of human ovarian cancer transplanted s.c. in nude mice.. Human ovarian cancer transplanted s.c. in nude mice model was established, then divided into 5 groups: control group, vehicle group, TNP group, CTX group and TNP + CTX group, different treatments were served from day 8 after transplantation and all mice were sacrificed after 28 days. The weights of the mice and the volumes of the tumors were measured respectively during the therapy time. Moreover, microscopy was done after H&E staining.. The growth inhibiting rates in the TNP and CTX group were 26.1% and 33.9% respectively; After combined, the rate was increased to 70.5%. There were no obvious decrease in the weight of all treated mice.. Treatment with TNP is an potentially useful method of antitumor therapy in ovarian cancer, although the inhibition effects were not obvious in small doses. Moreover, TNP could enhance the effectiveness of antitumor drug.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Division; Cyclohexanes; Cyclophosphamide; Drug Synergism; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; Sesquiterpenes; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Antitumor activity of angiogenesis inhibitor TNP-470 was evaluated in eight human cultured cell lines derived from choriocarcinoma: SCH, NUC-1, and GCH-1(m); ovarian cancer; TYK and Nakajima; and uterine endometrial cancer: HEC-6, HEC-50, and HEC-1-A. After 7-day culture with TNP-470, in medium at the concentration of 10(1) to 10(-2) micrograms/ml, the inhibition of growth was observed in all of the eight cell lines. The 50% inhibitory concentration of choriocarcinona cell lines was at an extremely low level compared to that of epithelial ovarian cancer and uterine endometrial cancer. In addition, the antitumor effect of this compound was studied in in vivo experiments using nude mice with tumors of GCH-1(m), NUC-1, or Nakajima cells. When the size of the transplanted tumor reached 100-200 mm3 in volume, 3, 10, or 30 mg/kg of TNP-470 was injected s.c. every other day. The inhibitory effect of TNP-470 was obtained by the administration of 10 and 30 mg/kg in GCH-1(m) and NUC-1 cells, respectively, while in Nakajima cells no significant effect was observed. In nude mice treated with 30 mg/kg of TNP-470, lung metastasis of GCH-1(m) cells was strongly inhibited both in the number and in the size of tumor nodules, indicating that the capillary growth in the originally developed tumor was also significantly reduced. These results suggest that the clinical setting using TNP-470 may be one of the promising treatments for the metastasis of tumor cells.

Topics: Animals; Cell Division; Choriocarcinoma; Cyclohexanes; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; Sesquiterpenes; Tumor Cells, Cultured