Usefulness of Tirapazamine as a Combined Agent in Chemoradiation and Thermo‐chemoradiation Therapy at Mild Temperatures: Reference to the Effect on Intratumor Quiescent Cells

Masunaga, Shin‐ichiro; Ono, Koji; Suzuki, Minoru; Kinashi, Yuko; Takagaki, Masao; Hori, Hitoshi; Kasai, Soko; Nagasawa, Hideko; Uto, Yoshihiro

doi:10.1111/j.1349-7006.2000.tb00982.x

Cited by 8 publications

(2 citation statements)

References 18 publications

(36 reference statements)

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“…Novel hypoxia‐sensitizers including tirapazamine, a reducing agent, and HIF‐1 inhibitor, including gene therapy, have recently been developed. ( 34–38 ) Moreover, several anticancer agents inhibit the proliferation of cancer cells by producing reactive oxygen species. ( 39,40 ) However, Rakicidin A does not act as a reductant because Rakicidin A has neither nitric oxide (NO) residues nor quinones in its structure.…”

Section: Discussionmentioning

confidence: 99%

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells

et al. 2010

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Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment. (Cancer Sci 2011; 102: 591-596) I n solid tumors, oxygen supply is frequently insufficient to adequately support rapid cell proliferation and angiogenesis, which leads to the development of hypoxic regions within the tumor.(1,2) These hypoxic regions are associated with altered cell metabolism, changes in cell cycling and increased resistance to cell death stimuli, and are often associated with a poor prognosis in cancer patients.(3-5) Therefore, the development of cytotoxic compounds that are effective in hypoxic conditions might overcome the therapeutic resistance of cancer cells in hypoxic micro environments.Bone marrow (BM) is known to have low levels of oxygen, and it has been suggested that the hematopoietic stem cells in the BM niche are protected from DNA damage induced by reactive oxygen species (ROS).(6,7) Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells caused by the constitutive activation of Bcr-Abl tyrosine kinase.(8) Treatment of CML has been markedly improved by the development of Abl tyrosine kinase inhibitors (TKI), but the complete eradication of CML cells may not be possible with TKI alone because they are largely ineffective against quiescent CML cells. (9)(10)(11)(12) Although it has not yet been confirmed, CML stem cells could reside in the BM niche because they exhibit characteristics similar to normal hematopoietic stem cells. Previously, we found that CML cells engrafted in the BM survived and proliferated in the severely hypoxic environment; furthermore, these hypoxiaadapted leukemic cells acquired a more primitive phenotype. (13) Recentl...

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Section: Discussionmentioning

confidence: 99%

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells

et al. 2010

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“…Actually, this combination was very effective in terms of enhancing the Q-cell response in radiotherapy or chemotherapy. 29,30) Recently, it was also reported that TPZ is still needed to enhance the Qcell response on chemoradiation using the mitotic spindle poison paclitaxel, because no radiosensitization effect in combination with paclitaxel was induced in Q tumor cells. 31) However, all these studies on combined treatment with MTH and/or TPZ were performed using mouse tumor cell lines with wild-type p53 status.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of combined treatment with mild temperature hyperthermia and/or tirapazamine in the treatment of solid tumors: its independence of p53 status

Masunaga¹,

Ono²,

Takahashi³

et al. 2003

Cancer Science

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t has been shown that the p53 tumor suppressor gene serves a critical role in maintaining genomic stability during a cell cycle checkpoint in G1 and the G2/M transition, 1) and as an effector of DNA repair 2) and apoptosis.3) Wild-type p53 is needed to activate apoptosis in sensitive cells in response to DNA damage.4) These actions of p53 are potentially critical in determining the effectiveness of ionizing radiation and/or chemotherapeutic agents. Actually, mutations in the p53 tumor suppressor gene have been shown to have an impact on the clinical course of several human cancers: patients with cancers harboring p53 mutations often have a worse prognosis than those with tumors harboring wild-type p53.5) Thus, the genetic and functional status of the p53 gene is thought to be an important factor in guiding therapeutic strategies for cancer patients.Meanwhile, mild temperature hyperthermia (MTH) was reported to increase the tumor response to radiation by improving tumor oxygenation through an increase in tumor blood flow, 6) and tirapazamine (TPZ, SR-4233, WIN 59075, 3-amino-1,2,4-benzotriazine-1,4-dioxide), a well-known bioreductive agent, has highly selective cytotoxicity toward hypoxic cells in in vivo tumor systems.7) In addition, MTH was also shown to enhance the tumor response, especially of the intratumor quiescent (Q) cell population, to chemotherapy. 8) Based on these reports, we have already demonstrated that combined treatment with MTH and/or TPZ is a promising modality in radiotherapy or chemotherapy from the viewpoint of the killing effect on intratumor Q tumor cells in comparison with the total (proliferating (P)+Q) tumor cell population, using several tumor systems with wildtype p53 status. 9)Accordingly, to investigate the usefulness of MTH and/or TPZ in the treatment of solid tumors consisting of cells with a mutated p53 status, we analyzed the killing effects of several DNA-damaging cytocidal treatments combined with or without MTH and/or TPZ on intratumor Q and total cells, employing two different tumor cell lines identical in genetic background except for p53 status 10) and our method for detecting the intratumor Q cell response in terms of the micronucleus (MN) frequency and apoptosis frequency. 9) As DNA-damaging cytocidal treatments, γ-ray irradiation, TPZ administration, cisplatin (CDDP) injection and paclitaxel (TXL) treatment were employed. Materials and MethodsCells, tumors and mice. The human head and neck squamous cell carcinoma cell line SAS (provided by JCRB, Tokyo) was cultured at 37°C in Dulbecco's modified Eagle's medium (DMEM) containing 20 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) and 12.5% fetal bovine serum in a conventional humified 5% CO 2 incubator. SAS cells show the phenotype of wild-type p53 in radiation-and heat-induced signal transduction.11) Plasmids pC53-248, which contains an mp53 gene (codon 248, from Arg to Trp) producing a dominant negative mp53 protein, and pCMV-Neo-Bam, which contains a neo-resistance marker, were provided by B. Vogels...

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Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione

Hori

Nagasawa

Uto

et al. 2004

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Usefulness of Tirapazamine as a Combined Agent in Chemoradiation and Thermo‐chemoradiation Therapy at Mild Temperatures: Reference to the Effect on Intratumor Quiescent Cells

Cited by 8 publications

References 18 publications

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells

Usefulness of combined treatment with mild temperature hyperthermia and/or tirapazamine in the treatment of solid tumors: its independence of p53 status

Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione

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