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Future Oncology (London, England) Dec 2013To provide therapeutic alternatives to intravenous colon chemotherapy major recent research is focusing on the development of oral chemotherapeutic agents with the... (Review)
Review
To provide therapeutic alternatives to intravenous colon chemotherapy major recent research is focusing on the development of oral chemotherapeutic agents with the intention to improve the quality of life of patients. Initially 5-fluorouracil was most commonly used for the treatment of colorectal cancer but currently oxaliplatin and irinotecan are also available. The majority of these new drugs are pyrimidines and their analogs. The rationale for using oral anticancer agents is discussed and new drugs, such as farnesyl protein transferase inhibitor S-1, rubitecan, ZD9331, MMI-166, eflornithine, sulindac, and oral camptothecin analogs, among others, are presented with the results of their preclinical and clinical developments. This article focuses on the advancement of clinical development and also discusses the relative merits and demerits of these agents. The accelerated approval of these agents by regulatory authorities is supported by survival benefit, response rate and time to progression.
Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Humans
PubMed: 24295419
DOI: 10.2217/fon.13.137 -
Colloids and Surfaces. B, Biointerfaces Apr 2014The aim of this study was to develop a new polymeric micelle delivery system for antitumor drugs. An amphiphile of methoxypoly(ethylene glycol)-histidine-di(cinnamic...
The aim of this study was to develop a new polymeric micelle delivery system for antitumor drugs. An amphiphile of methoxypoly(ethylene glycol)-histidine-di(cinnamic acid) (PEGHC) with a small lipophilic moiety instead of a hydrophobic biodegradable polymer chain was synthesized and characterized. The PEGHC self-assembled into micelles. The critical micelle concentration (CMC) was tested. 9-Nitro-20(s)-camptothecin (9-NC) was used as a model drug for encapsulation. The size and morphology of both blank and 9-NC loaded micelles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The release profile of 9-NC loaded micelles was studied. HepG2 liver cancer cells were incubated with the drug-loaded micelles to investigate the in vitro anticancer efficiency. The results showed that the 9-NC loaded micelles exhibited high accumulated release rate (>85%) and efficient in vitro anticancer activity.
Topics: Antineoplastic Agents; Camptothecin; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Micelles; Molecular Structure; Polymers; Structure-Activity Relationship
PubMed: 24268560
DOI: 10.1016/j.colsurfb.2013.10.032 -
Cancer Chemotherapy and Pharmacology Oct 2013Since the carboxylate form could be regarded as a possible "source" of lactone form, the optimum ratio of lactone should be determined for the administration of...
PURPOSE
Since the carboxylate form could be regarded as a possible "source" of lactone form, the optimum ratio of lactone should be determined for the administration of camptothecin (CPT) analogues such as 9-nitrocamptothecin (9-NC).
METHODS
9-NC solutions with different lactone ratios (100, 75, 50, 25 and 0 %) were obtained by the change of pH. The resultant 9-NC solution and corresponding blank solvent were intravenously injected to mice to evaluate toxicity. The S180 tumor-bearing mice were intravenously administered 9-NC solutions with different lactone ratios, and the antitumor efficacy and toxicity were compared. The tissue distribution of lactone and total (the total of lactone and carboxylate forms) 9-NC was also investigated as a function of lactone ratio.
RESULTS
Toxicity of 9-NC was found to be increased with the increase in lactone ratio. The tumor inhibitory rates of 9-NC solution were determined to be 64.17, 60.43, 42.78, 41.71 and 8.60 % for 100, 75, 50, 25 and 0 % lactone ratio, respectively. The lactone stability of 9-NC in most tissues was found to be higher than in plasma. In tumor and plasma, whether for lactone or total 9-NC AUC values, there was no difference between 100 and 75 % groups.
CONCLUSIONS
Although carboxylate form of CPTs is inactive, the administration of carboxylate form in an appropriate ratio is active as a result of its conversion to lactone form in vivo.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Camptothecin; Hydrogen-Ion Concentration; Injections, Intravenous; Lactones; Mice; Mice, Inbred ICR; Sarcoma 180; Tissue Distribution; Toxicity Tests
PubMed: 23934323
DOI: 10.1007/s00280-013-2259-x -
Journal of Pharmaceutical Sciences Oct 2013Solid-state properties and physicochemical characteristics of 9-nitrocamptothecin (9NC) were investigated with a view of molecular and bulk level understanding of its...
Solid-state properties and physicochemical characteristics of 9-nitrocamptothecin (9NC) were investigated with a view of molecular and bulk level understanding of its poor aqueous solubility and hydrolytic instability that prevent efficient drug delivery and pharmacological activity. 9NC bulk drug substance was found to be a nonhygroscopic, yellowish crystalline solid with long rectangular prism-shaped particle morphology and a sharp melting point at 264°C. Hydrolysis of 9NC-lactone occurs above pH 4, whereas complete conversion of lactone to carboxylate was recorded above pH 8. At saturated conditions, appreciable concentrations of 9NC-lactone were detected at pH as high as 11. 9NC undergoes oxidation in the presence of dimethyl sulfoxide with formation of 9NC-N-oxide. The total solubility of lactone and carboxylate forms of 9NC in deionized water was found to be less than 5 μg/mL, whereas the solubility of 9NC-lactone in aqueous acidic media was determined to be approximately 2.5 μg/mL. Incorporation of 10% pluronic copolymers P123, F127, and F68 in 10 mM HCl increased 9NC solubility by 13-fold, eightfold, and fivefold, respectively. The thermodynamic stability of drug-loaded pluronic micelles was evaluated under isothermal variable volume conditions and found F127, among all poloxamers, to offer the best hydrolytic protection efficacy for 9NC.
Topics: Camptothecin; Drug Stability; Hydrogen-Ion Concentration; Hydrolysis; Lactones; Micelles; Oxidation-Reduction; Poloxamer; Polymers; Solubility; Temperature; Thermodynamics; Water
PubMed: 23873658
DOI: 10.1002/jps.23671 -
Cancer Biology & Therapy Jul 2013Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by...
Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chordoma; Drug Screening Assays, Antitumor; Humans; Small Molecule Libraries
PubMed: 23792643
DOI: 10.4161/cbt.24596 -
Anti-cancer Agents in Medicinal... Sep 2012All chemotherapeutic agents currently in use have a narrow window of therapeutic index of 1 to 1.2. Camptothecin ester compounds are reported to have a wider therapeutic...
All chemotherapeutic agents currently in use have a narrow window of therapeutic index of 1 to 1.2. Camptothecin ester compounds are reported to have a wider therapeutic index when being used to treat human xenografts in nude mice. As a continuous effort in searching for better chemotherapeutic agents for treating cancers, new haloalkyl camptothecin and 9-nitrocamptothecin ester derivatives 2a-b and 3a-d were prepared by respective acylation of camptothecin 1a and 9-nitrocamptothecin 1b with the corresponding acylating agents. These new derivatives were tested in vitro against 8 human cancer cell lines using 7 different concentrations ranging from 5 to 300 nM and also in vivo against various types of human tumor xenografts grown in nude mice. Most of these new compounds started showing inhibitory effects on the growth of 8 cancer cell lines at concentration of 80 nM and achieved greater than 70% inhibitions against these cell lines when the concentration increased to 300 nM. Compound 2a and 3a showed good activity against human tumor xenografts in nude mice. Compared to mother compound camptothecin, 3a was much less toxic in mice with a better therapeutic index, having the potential to be further developed as a safer treatment for cancers.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Cell Line, Tumor; DNA Topoisomerases, Type I; Esters; Humans; Mice; Mice, Nude; Models, Molecular; Neoplasms; Prodrugs; Transplantation, Heterologous
PubMed: 22583427
DOI: 10.2174/187152012802650219 -
PloS One 2011Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with...
BACKGROUND
Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms.
METHODOLOGY/PRINCIPAL FINDINGS
We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo.
CONCLUSIONS/SIGNIFICANCE
In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.
Topics: Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Stability; Female; Gene Expression Regulation, Neoplastic; Humans; Liposomes; Liver Neoplasms; Mice; Solubility; Ultrasonics; Water; Xenograft Model Antitumor Assays
PubMed: 21695227
DOI: 10.1371/journal.pone.0021064 -
International Journal of Pharmaceutics Aug 2011The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-β-cyclodextrin (9-NC/HP-β-CD) complex on tumor-bearing...
The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-β-cyclodextrin (9-NC/HP-β-CD) complex on tumor-bearing mice. The in vitro anti-tumor activity was tested by MTT assay. Our study revealed that the 9-NC/HP-β-CD complex showed significant anti-tumor activity towards Skov-3, MCF-7, HeLa and S180 cell lines with IC(50) values of 0.24 ± 0.09, 0.59 ± 0.20, 0.83 ± 0.11, and 6.30 ± 2.42 μg/ml, respectively, significantly superior to the free 9-NC. The in vivo therapeutic efficacy was investigated in ICR mice bearing mouse sarcoma S180. Both the high (3mg/kg) and low (1mg/kg) doses of 9-NC/HP-β-CD complex demonstrated high inhibition ratio of tumor growth (>75%). The subacute toxicity test was performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters (total bilirubin, alanine transferase, aspartate transferase, blood urea nitrogen and creatinine), and the results indicated the good safety profile of the complex. Taken together, the results suggested that the 9-NC complexed in HP-β-CD, instead of dissolved in the organic solvent, presented significant anti-tumor activity and low toxicity for the treatment of cancer.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adjuvants, Pharmaceutic; Animals; Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Compounding; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred ICR; Sarcoma 180; Toxicity Tests, Chronic; Xenograft Model Antitumor Assays; beta-Cyclodextrins
PubMed: 21645594
DOI: 10.1016/j.ijpharm.2011.05.056 -
Journal of Pharmaceutical Sciences May 2011
Topics: Antineoplastic Agents; Camptothecin; Drug Compounding
PubMed: 21374629
DOI: 10.1002/jps.22424 -
Cancer Chemotherapy and Pharmacology Apr 20119-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of...
PURPOSE
9-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of 9-nitrocamptothecin in patients with advanced solid tumors.
METHODS
The 23 patients for a single-dose pharmacokinetic experiment were divided into 3 dosing cohorts. The dosage of 9-nitrocamptothecin capsule was 1.25, 1.5 and 1.75 mg/m(2), respectively. The 8 patients for a multiple-dose pharmacokinetic study were orally administered 9-nitrocamptothecin 1.5 mg/m(2) for 5 consecutive days. Determination of the plasma concentration of 9-nitrocamptothecin was performed by high-performance liquid chromatography-ultraviolet detector technique, and determination of plasma concentration of 9-aminocamptothecin was performed by high-performance liquid chromatography-fluorescence detector technique.
RESULTS
In the single-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin C(max) were 94.49 ± 41.38, 115.56 ± 63.27 and 147.57 ± 38.19 ng/mL; AUC(0-36) were 877.14 ± 360.90, 961.33 ± 403.58 and 1,189.75 ± 405.80 ng h/mL, respectively; the mean ± SD 9-aminocamptothecin C(max) were 12.85 ± 6.46, 10.72 ± 6.58 and 28.74 ± 31.94 ng/mL; AUC(0-36) were 157.61 ± 111.61, 88.71 ± 39.51 and 173.52 ± 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin AUC(ss) was 907.04 ± 736.47 ng h/mL, C(max) was 85.98 ± 47.52 ng/mL, C(min) was 18.91 ± 22.50 ng/mL, C(av) was 37.79 ± 30.69 ng/mL, DF was 2.16 ± 0.87; the mean ± SD 9-aminocamptothecin AUC(ss) was 442.73 ± 308.39 ng h/mL, C(max) was 34.83 ± 18.31 ng/mL, C(min) was 10.32 ± 6.95 ng/mL, C(av) was 18.45 ± 12.85 ng/mL, DF was 1.34 ± 0.42. Comparing single-dose 1.5 mg/m(2) group with multiple-dose 1.5 mg/m(2) group, no significant difference was observed in 9-NC pharmacokinetic parameters, but with respect to the metabolite, significant differences were observed in C(max) and AUC. The toxicity of 9-NC varied from mild to moderate. No grade 3 or grade 4 toxicity was observed during the study. There was 2- to 13-fold variabilities in 9-NC and 9-AC exposure among different patients for any given dose of 9-NC.
CONCLUSIONS
All participants had good tolerance throughout the study. 9-NC and 9-AC exposure did not increase proportionally to the dose ranging from 1.25 to 1.75 mg/m(2). After 5-day continuous administration, accumulation was observed in the metabolite 9-AC, but not in 9-NC.
Topics: Administration, Oral; Adult; Antineoplastic Agents; Area Under Curve; Camptothecin; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Time Factors
PubMed: 21191594
DOI: 10.1007/s00280-010-1546-z