Cancer Chemotherapy by Liposomal 6-[[2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one Dihydrochloride (TAS-103), a Novel Anti-cancer Agent.

A novel quinoline derivative, TAS-103 ( Fig. 1), has many attractive biological functions: i) it inhibits both topoisomerase (topo) I and topo II; ii) it stabilizes both topo I-and topo II-DNA cleavable complexes; iii) it shows potent cytotoxic effects in vitro; iv) it shows high antitumor activities against subcutaneously-implanted murine and human tumors in vivo, as well as various lung-metastatic murine tumors. 1)However, it is unclear whether TAS-103 will show the similar level of activity against tumors in patients. In this setting, the chemosensitivity test is expected to show its potential for predicting activity of anticancer agents against human tumors.Various in vitro drug sensitivity tests have been used to assay the responsiveness of tumors to anticancer agents. 2-7)Among various techniques, the colony-forming assay may be the most widely applied in vitro assay for clinical use. 8) In a large study of prospective trials using colony-forming assay, it was shown that true-positive rate was 60% and true-negative rate was 85% based on clinical response. 9) Although this assay seems to be reliable for predicting the clinical response to chemotherapies, it is time-and cost-consuming, laborintensive, and suffers from a low success rate.10) In addition, this assay requires preparations of a single-cell suspension, which renders considerable damage to the tumor cells.We have used direct in vitro measurements of apoptosis as a chemosensitivity test. Two different methods have been employed; morphological examinations of the nuclear damage, such as the chromatin condensation or degradation, 5) and flow cytometric (FCM) analysis of DNA integrity which shows apoptosis as the sub-G1 population.11) The FCM assay Correlations between TAC and PPC were examined for 16 clinically available anticancer agents, and it was found that TAC at 7n (the modified Fibonacci's dose-escalation scheme) of 14 drugs corresponded well with each one-tenth of PPC. By defining a 30% or more reduction in the integrated diploid peak as effective and a 60% or more reduction as definitely effective, TAS-103 at 5 m mg/ml (7n) showed significantly higher effective rates and definitely effective rates than those of all other investigational new drugs, as well as almost all clinically available anticancer agents, against various malignancies, including nonsmall cell lung cancer, brain tumor and renal cancer. These results strongly suggest that TAS-103 will be expected to show excellent antitumor activities against a wide range of human tumors.

Section: De (%)mentioning

confidence: 99%

Promising Antitumor Activity of a Novel Quinoline Derivative, TAS-103, against Fresh Clinical Specimens of Eight Types of Tumors Measured by Flow Cytometric DNA Analysis

Fujimoto

2007

“…65) In fact, liposomalization of an anti-cancer agent enhanced the anticancer effect because of longcirculation in the bloodstream and the subsequent accumulation in tumor tissue due to enhanced permeability and retention (EPR) effect. [66][67][68][69] Furthermore, angiogenic endothelial cells are believed to express several specific molecules, which are known or unknown, in comparison with normal endothelial cells. Therefore, these distinct marker molecules may provide active targeting guides for anti-neovascular therapy.…”

Section: Anti-neovascular Therapy (Anet)mentioning

confidence: 99%

Cancer Anti-angiogenic Therapy

Shimizu

Oku

2004

Self Cite

Tumor angiogenesis affords new targets for cancer therapy, since inhibition of angiogenesis suppresses tumor growth by cutting out the supply of oxygen and nutrients. Anti-angiogenic therapy is thought to be free of the severe side effects that are usually seen with cytotoxic anticancer drugs. Furthermore, anti-angiogenic therapy is thought not only to eradicate primary tumor tissues, but also to suppress tumor metastases. However, it is uncertain whether this therapy causes tumor regression because it inhibits only angiogenic events. Recently, a novel anti-angiogenic therapy called anti-neovascular therapy (ANET) has become notable. This therapy inflicts indirect lethal damage on tumor cells by damaging newly formed blood vessels using anti-cancer drugs targeting the angiogenic vasculature, since cytotoxic anti-cancer drugs cause damage to proliferating neovascular endothelial cells as well as tumor cells. Moreover, neovascular endothelial cells would not be expected to acquire drug-resistance. Traditional chemotherapy, which directly targets tumor cells, has potential problems such as low specificity and severe side effects. On the contrary, in ANET, severe side effects may be suppressed, since traditional anti-cancer agents are delivered to the neovessels by DDS technology. Besides the usage of DDS technology, antineovascular scheduling of chemotherapy, or metronomic-dosing chemotherapy, has also been attempted in which anti-cancer drugs are administered on a schedule to damage neovessels. In this review, we describe traditional anti-angiogenic therapy and ANET. We also discuss anti-angiogenic cancer photodynamic therapy (PDT), since PDT is clinically applied to treat age-related macular degeneration (AMD), in which uncontrolled angiogenesis occurs.

“…[23][24][25] Furthermore, liposomes with long circulating characteristics are known to accumulate in interstitial spaces of tumor tissues of which blood vessels are highly permeable. 26,27) For the purpose of DDS, liposomes having rather rigid lipid bilayer are favorable, and they are usually composed of phospholipids with saturated fatty acyl chains and cholesterol. On the other hand, liposomes have been used for the injection of hydrophobic drugs, since hydrophobic materials can be encapsulated into the lipid bilayer of the liposomes.…”

Section: )mentioning

confidence: 99%

Antitumor Activity of Liposomal Naphthoquinone Esters Isolated from Thai Medicinal Plant: Rhinacanthus nasutus KURZ.

Siripong

Yahuafai

Shimizu

et al. 2006

Self Cite

Rhinacanthus nasutus KURZ. (family Acanthaceae), has been used in Thai traditional medicine for the treatment of various diseases such as eczema, pulmonary tuberculosis, herpes, hepatitis, diabetes, hypertension and various skin diseases, and its active components were widely investigated. 1-7)R. nasutus KURZ. has also been used for cancer treatment. [8][9][10] The main bioactive compounds were revealed to be naphthoquinone; rhinacanthins (A-D, G-Q), rhinacanthone and lignan groups. [1][2][3][4][5][6][7][8]10,11) Antitumor activity of R. nasutus KURZ. extracts,8) and that of rhinacanthone in the in vivo study were reported. 11) We previously reported that rhinacanthins-M, -N and -Q and related naphthoquinone esters as well as synthetic compounds, 1,2-naphthoquinones and 1,4-naphthoquinones, selectively suppressed the growth of KB, HeLa and HepG2 human cancer cells, and normal Vero cells. 12,13) We also performed mechanistic study and observed that synthetic rhinacanthins-N and -Q inhibited DNA topoisomerase II.13) A naphthoquinone compound b-lapachone, that was also derived from natural products and has a similar structure to rhinacanthone, was reported to be a potent inhibitor of DNA topoisomerase I and II, [14][15][16] and to induce apoptosis of various cancer cells. [17][18][19][20][21] Recently, we observed that rhinacanthins-C, -N and -Q suppressed human cervical carcinoma HeLaS3 cells through induction of apoptosis. 22)Therefore, in the present study, we attempted to determine actual antitumor activity of rhinacanthins in tumor-bearing mice.Since rhinacanthins-C, -N and -Q are hydrophobic compounds, they are not able to inject into bloodstream without solubilization. For in vivo use of the drugs, we attempted to solubilize them in liposomes. By the way, liposomes have been widely used in the field of drugs delivery systems (DDS): Liposomalization reduces side effects and toxicities of drugs encapsulated, and improves their bioavailability. Therefore, liposomes tended to be used for cancer treatment, since most of anticancer drugs accompany severe side effects. [23][24][25] Furthermore, liposomes with long circulating characteristics are known to accumulate in interstitial spaces of tumor tissues of which blood vessels are highly permeable. 26,27) For the purpose of DDS, liposomes having rather rigid lipid bilayer are favorable, and they are usually composed of phospholipids with saturated fatty acyl chains and cholesterol. On the other hand, liposomes have been used for the injection of hydrophobic drugs, since hydrophobic materials can be encapsulated into the lipid bilayer of the liposomes. For example, Visudyne, a liposomal formulation of benzoporphyrin derivative monoacid ring A (BPD-MA), is being used clinically in photodynamic therapy for age-related macular degeneration. In Visudyne, liposomes are used as a "solvent" of BPD-MA for the purpose of injection of the drug into bloodstream.28) In such case, liposomes having rather fluid lipid bilayer are used, and the injected drug in the bloodstream is t...