Current molecular design of intelligent drugs and imaging probes targeting tumor-specific microenvironments

Tanabe, Kazuhito; Zhang, Zhouen; Itô, Takeo; Hatta, Hiroshi; Nishimoto, Sei‐ichi

doi:10.1039/b711244k

Cited by 52 publications

(24 citation statements)

References 127 publications

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“…Several researchers reported that wide varieties of bioreduction-activatable prodrugs such as tegafur (Ftorafur) [1-(2-tetrahydrofuranyl)-5-fluorouracil] derivatives [2][3][4], 1-alkylcarbamoyl-5-fluorouracils [5,6], and 5-fluoro-2-deoxyuridine (5-FdUrd) derivatives [7,8] have been developed as anticancer agents [9,10]. Bioreductive prodrugs can be activated into their radical intermediates, which are oxidized to the prodrug under aerobic conditions.…”

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confidence: 99%

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

et al. 2011

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5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N(1)-C(5)-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis.

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confidence: 99%

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

et al. 2011

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“…Molecular imaging presents exciting opportunities for selective detection of specific cell populations, such as those bearing markers of disease (1, 2). Cyclooxygenase-2 (COX-2) is an attractive target for molecular imaging because it is expressed in only a few normal tissues and is greatly up-regulated in inflamed tissues as well as many premalignant and malignant tumors (3, 4).…”

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confidence: 99%

Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents

et al. 2010

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Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2-specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2-expressing human cancers, such as those in the esophagus, oropharynx, and colon.Cancer Res; 70(9); 3618-27. ©2010 AACR.

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“…Anticancer agents can directly interfere with a cellular process that occurs at different rates or is differentially important in the two types of cells, or they can be preferentially delivered to the cancer cells. One property of cancer cells in solid tumors that can be used to preferentially target them instead of normal cells is their relatively hypoxic nature Tanabe et al, 2007). The poor vascularization resulting from the rapid growth of tumors means that cells within the tumor are less well oxygenated than normal cells.…”

Section: Introductionmentioning

confidence: 99%

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

Nishida

Lee²,

Montellano³

2010

Molecular Pharmacology

104

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AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.

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Current molecular design of intelligent drugs and imaging probes targeting tumor-specific microenvironments

Cited by 52 publications

References 127 publications

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1

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