<i>In vitro</i> Antitumor Activity of TAS‐103, a Novel Quinoline Derivative That Targets Topoisomerases I and II

Aoyagi, Yoshimi; Kobunai, Takashi; Utsugi, Teruhiro; Oh‐hara, Tomoko; Yamada, Yuji

doi:10.1111/j.1349-7006.1999.tb00786.x

Cited by 39 publications

(28 citation statements)

References 28 publications

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“…[8][9][10][11][12] Various anti-tumor agents targeting topoisomerase I or II have been developed such as camptothecin and etoposide, while TAS-103 inhibits both topoisomerase I and II at low doses and expresses high anti-tumor activity against various human tumor cells. [4][5][6] Furthermore, TAS-103 effectively inhibited growth of tumor cells in vivo that acquire the resistance against topoisomerase II-targeting agents. [12][13][14][15] Thus, TAS-103 is expected to be used clinically.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…A549/TAS was distinguishable from MDR cells, because of the lack of overexpression of P-gp, a finding which is supported by the earlier report that MDR cell lines (P388/ADR, MCF-7/Ad10 and KB/VCR cells) did not show cross-resistance to TAS-103. 4) Decreased intracellular accumulation of TAS-103 may be related to an increased expression of MRP in A549/TAS cells. It has been reported that the increased expression of MRP in the cells was associated with a decreased accumulation of VP-16 or glutathione.…”

Section: Intracellular Accumulation Of Tas-103mentioning

confidence: 99%

“…3) The cytotoxic activity of TAS-103 appeared to be unaffected by overexpression of P-gp, a protein involved in multidrug resistance (MDR). 4) The above properties justified further clinical evaluation, which is in progress in the USA.…”

Section: Intracellular Accumulation Of Tas-103mentioning

confidence: 99%

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Establishment and Characterization of 6‐[[2‐(Dimethylamino)ethyl]amino]‐3‐hydroxy‐7H‐indeno[2,1‐c]quinolin‐7‐one dihydrochloride (TAS‐103)‐resistant Cell Lines

Aoyagi

Kobunai

Utsugi

et al. 2000

Japanese Journal of Cancer Research

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Key words: TAS-103 -Topoisomerases -ResistanceThe DNA topoisomerases (Topo), nuclear enzymes controlling DNA topology, have been identified as important targets for cancer chemotherapy. CPT-11 and topotecan were developed as inhibitors of Topo I, while VP-16, VM-26 and some intercalating agents widely used in cancer chemotherapy (adriamycin (ADR), amsacrin, mitoxantrone), were identified as Topo II inhibitors.1, 2) The novel anticancer agents targeting both Topo I and Topo II are now considered as a promising approach in finding clinically more effective antitumor agents than agents targeting only one Topo. We have reported that 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) inhibited Topo I and Topo II in in vitro enzymatic assays, and showed potent antitumor activity against various human tumor xenografts and metastatic tumors.3, 4) TAS-103 is under clinical evaluation in the USA.In this study, to elucidate the mechanism of action of TAS-103, we have established TAS-103-resistant cell lines and characterized their cross-resistance to various anticancer agents, the changes in Topo levels and the intracellular accumulation of TAS-103. Cell lines resistant to Topo inhibitors have been reported to acquire the resistance because of reduced expression levels or mutation of the enzymes.5-11) The resistance phenotype was associated with alteration in both Topo I and Topo II following sequential exposure to either Topo I or Topo II inhibitor. 12)Another possible mechanism of resistance is a decrease of drug accumulation caused by the presence of drug transporter proteins (P-glycoprotein (P-gp) and multidrug resistance related protein). [13][14][15] The multifunctional changes, decreased levels of Topo I and/or Topo II and intracellular accumulation of TAS-103 should be taken into account as factors contributing to differences in the mechanisms of resistance among various cell lines.

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Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

Denny¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents remain important DNA alkylators. Methotrexate, and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. Cytosine arabinoside and more recent compounds like gemcitabine, fludarabine, cladribine, and pentostatin inhibit DNA polymerase action during DNA synthsis. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs targeted at DNA. The increasing power of organic chemistry increasingly allows the synthesis of close analogs of cytotoxic, but complex, natural products as potential drugs; recent examples are synthetic analogs of the duocarmycins and the epothilones. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy, or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive non‐tumor cell populations.

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In vitro Antitumor Activity of TAS‐103, a Novel Quinoline Derivative That Targets Topoisomerases I and II

Cited by 39 publications

References 28 publications

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.

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.

Establishment and Characterization of 6‐[[2‐(Dimethylamino)ethyl]amino]‐3‐hydroxy‐7H‐indeno[2,1‐c]quinolin‐7‐one dihydrochloride (TAS‐103)‐resistant Cell Lines

Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

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