Potential Usage of Liposomal 4.BETA.-Aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53) for Cancer Chemotherapy.

Shimizu, Kosuke; Takada, Miki; Asai, Tomohiro; Irimura, Kenji; Baba, Kazuhiko; Oku, Naoto

doi:10.1248/bpb.25.783

Cited by 13 publications

(6 citation statements)

References 16 publications

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“…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

Biological & Pharmaceutical Bulletin

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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.

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Section: Anti-neovascular Therapy (Anet)mentioning

confidence: 99%

Cancer Anti-angiogenic Therapy

Shimizu

Oku

2004

Biological & Pharmaceutical Bulletin

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“…Although the solubility problem had been resolved, toxicity issues remain a challenge for the semisynthetic glucoconjugates. Furthermore, some non-sugar substituted PPT derivatives were developed, e.g., NK-611 ( 6 ), GL-331 ( 7 ), NPF ( 8 ), TOP-5 ( 9) , and QS-ZYX-1-61 ( 10 ), which displayed a better pharmacology profile, exhibited excellent anti-tumor activity and reached clinical trials for the treatment of a broad spectrum of tumors (Utsugi et al, 1996; Shimizu et al, 2002; You, 2005; Lv and Xu, 2011; Kamal et al, 2015; Liu et al, 2015). These novel derivatives were obtained by modifying at the C-4 position of PPT/DPPT.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

Wei

Chen

et al. 2019

Front. Chem.

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A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound 12h showed high activity with IC 50 values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC 50 : 8.4 to 78.2 μM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC 50 values of 2.7 and 49.1 μM, respectively. Compound 12g displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, 12g induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that 12g merits further optimization and development as a new podophyllotoxin-derived lead compound.

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“…7) We do not know the reason for this discrepancy at present, although liposomal accumulation in tumor tissue does not mean the availability of encapsulated agents to tumor cells. Since liposomal TAS-103 was as toxic as free TAS-103 in vitro (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…TAS-103 encapsulation was performed as described previously. 7) Briefly, liposomal solution was neutralized with 0.5 M sodium carbonate and diluted with 20 mM HEPES-buffered saline, pH 7.5, to establish a pH gradient between inner and outer solutions of liposomes. Then, the liposomes were incubated with 20 mM HEPES-buffered TAS-103 solution at 60°C for 30 min to load TAS-103 into the internal aqueous space of liposomes.…”

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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.

Shimizu

Takada

Asai

et al. 2002

Biological & Pharmaceutical Bulletin

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Most anti-cancer agents express not only primary therapeutic effects but also unfavorable side effects because of their low tumor-selectivity. To improve this problem, a drug delivery system (DDS) which enables delivery of a certain agent to the target organ is being used in cancer chemotherapy. Liposomes have been used as carriers of anti-cancer agents, since they can effectively deliver the entrapped materials to the interstitial spaces of tumor tissue of which blood vessels are highly permeable. Furthermore, the liposomal surface can be modified with certain targeting molecules such as antibodies and peptides, and they are expected to be used as active targeting tools.1) In fact, liposomalization of anti-tumor agents has been studied extensively and shown to increase their plasma concentration, to improve their distribution, and to decrease the side effects. 2,3) In this study, we investigated the anti-tumor efficacy of 6-[[2-(dimethylamino) ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), a novel quinoline derivative, in a liposomal formulation. TAS-103 is known to show high and broad anti-tumor activity against murine and human tumor cells by inhibiting both topoisomerase I and II activity. [4][5][6] Like other cytotoxic anti-tumor drugs, improvement in the tumor selective delivery of the agent may make it beneficial for the practical use. For this reason, we encapsulated TAS-103 into liposomes and evaluated the antitumor efficacy of liposomal TAS-103. MATERIALS AND METHODSMaterials TAS-103 is the product of Taiho Pharmaceutical Co., Ltd. (Tokushima, Japan). Dipalmitoylphosphatidylcholine (DPPC) was a gift from Nippon Fine Chemical Co. Ltd. (Takasago, Hyogo, Japan). Cholesterol was purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.), and reduced Triton X-100 was from Aldrich Chemical Co. (Milwaukee, WI, U.S.A.).Preparation of Liposomal TAS-103 DPPC and cholesterol (2 : 1 as a molar ratio) dissolved in chloroform were dried under reduced pressure and stored in vacuo for at least 1 h to prepare thin lipid film. Liposomes were formed by hydration with 0.3 M citric acid solution adjusted to pH 4.0, frozen and thawed for three cycles using liquid nitrogen, and sonicated in a bath-type sonicator for 10 min. The resulting liposomes were sized by three extrusions through a polycarbonate membrane filter with a pore size of 100-nm. TAS-103 encapsulation was performed as described previously. 7)Briefly, liposomal solution was neutralized with 0.5 M sodium carbonate and diluted with 20 mM HEPES-buffered saline, pH 7.5, to establish a pH gradient between inner and outer solutions of liposomes. Then, the liposomes were incubated with 20 mM HEPES-buffered TAS-103 solution at 60°C for 30 min to load TAS-103 into the internal aqueous space of liposomes. Liposomal TAS-103 solution was ultracentrifuged thrice at 90000ϫg for 15 min to remove any untrapped TAS-103 if present. Then, the liposomal TAS-103 was resuspended in phosphate-buffered saline (PBS), pH 7.4. For the evaluation of encaps...

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Potential Usage of Liposomal 4.BETA.-Aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53) for Cancer Chemotherapy.

Cited by 13 publications

References 16 publications

Cancer Anti-angiogenic Therapy

Cancer Anti-angiogenic Therapy

Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

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.

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