Preclinical study on hypoxic radiosensitizing effects of glycididazole in comparison with those of doranidazole in vitro and in vivo

  • Authors:
    • Hironobu Yasui
    • Nobuo Kubota
    • Junko Nishizumi
    • Yuri Sakai
    • Tohru Yamamori
    • Osamu Inanami
  • View Affiliations

  • Published online on: November 23, 2017
  • Pages: 1993-1998
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations


To overcome the radioresistance of hypoxic cells in solid tumor, numerous types of radiosensitizers specifically against them have been developed. Glycididazole has a chemical structure in which two metronidazole forms are combined, and is widely used as a hypoxic radiosensitizer in China. However, a detailed investigation of its radiosensitizing properties has not been performed. The present study reported a comparative assessment of glycididazole and doranidazole, another hypoxic radiosensitizer. All experiments were performed using the murine squamous cell carcinoma cell line SCCVII. Prior to X‑irradiation, the cells were treated with the test drugs at concentrations of 10 mM and 200 mg/kg in vitro and in vivo, respectively. Uptake and their intratumor chemical forms were analyzed by high performance liquid chromatography (HPLC). Both drugs enhanced the reproductive cell death induced by X‑irradiation under hypoxia. However, the growth delay assay of the transplanted tumor revealed the combination of X‑irradiation and glycididazole showed a similar antitumor effect to that of X‑irradiation alone, whereas doranidazole significantly sensitized the cells to X‑irradiation. HPLC analysis revealed that incorporated glycididazole was decomposed to metronidazole and was therefore present at a lower concentration compared with that of doranidazole. The decomposition of glycididazole to metronidazole reduced its radiosensitizing efficiency in vivo. Elucidation of the kinetics of drugs containing metabolizable chemical forms is necessary for the optimization of clinical treatment.


Tumor hypoxia is recognized as a well-known obstacle to radiotherapy due to the limitation of oxygen effect, i.e., oxygen-dependent sensitization of radiation efficiency (1). To reduce the radioresistance of hypoxic tumors, several strategies, such as fractionated radiotherapy, increased oxygen delivery, hypoxia inducible factor (HIF)-1 inhibitors, and radiosensitizers, have been developed (2). Since the introduction of misonidazole in the 1970s, numerous hypoxic cell radiosensitizers have been screened; several have undergone clinical evaluation (3). However, clinical trials with nitroimidazole derivatives have demonstrated their limited therapeutic benefit and remain inconclusive. Furthermore, misonidazole and etanidazole, the well-known nitroimidazole derivatives, induced undesirable side effects such as neurotoxicity (4). Additionally, the low tolerable dose produced an inconclusive outcome and restricted the clinical use of these drugs. In contrast to these results, a Danish trial of nimorazole, another radiosensitizer, significantly improved the radiotherapy of squamous head and neck cancers without major side effects (5,6). In these trials, clinically relevant hypoxia markers allowed the identification of patients that benefit from the combination of nimorazole and radiotherapy.

Furthermore, doranidazole [1-(1′,3′,4′-trihydroxy-2′-butoxy)-methyl-2-nitroimidazole, PR-350; Fig. 1] was established in Japan; its structure is intended to reduce neurotoxicity owing to its impermeability across the blood-brain barrier (BBB) (7). The radiosensitizing effect of this compound under hypoxia has been clarified in vitro (810) and in vivo (8,9,11,12). Recently, our group demonstrated the radiosensitizing effect of doranidazole on C6 rat intracranial glioma, which shows wide range of hypoxia and disruption of the BBB (13). Based on these studies, a phase I/II trial against locally advanced non-small-cell lung cancer (14) and phase III trials of doranidazole against advanced pancreatic cancer (15,16) were performed. Some studies demonstrated that doranidazole treatment after irradiation significantly improved the local tumor control and overall survival. These recent clinical reports have encouraged the further development and improvement of nitroimidazoles.

In China, sodium glycididazole, a nitroimidazole derivative with a chemical structure containing a dimer of metronidazole (Fig. 1), was designed, screened, and studied by the Second Military Medical University (17). There are several literature reports in Chinese that indicate the radiation-enhancing potential of glycididazole. In addition, glycididazole was reported to have radiosensitizing and chemosensitizing effects in clinical trials (1719) and is marketed and used clinically. However, there are few preclinical studies and no investigations have been performed to evaluate the radiosensitizing efficacy of glycididazole in comparison with that of other nitroimidazole derivatives. Therefore, in this study, we aimed to evaluate the radiosensitizing effects of glycididazole and doranidazole on tumor cells with different oxygenation conditions in vitro and on the tumor growth of subcutaneous xenografts in vivo.

Materials and methods


Glycididazole was purchased from Luye Pharma Group Co., Ltd, (Beijing, China). Doranidazole was supplied by Pola Pharma Inc. (Tokyo, Japan). Ultrapure N2 gas (99.999%) was obtained from Air Water Technical Supply (Ishikari, Japan). All other chemicals were purchased from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan), unless otherwise stated.

Cell culture

Murine squamous cell carcinoma SCCVII cells were grown in α-MEM (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS; Filtron Pty. Ltd., Brooklyn, Australia). Cells were maintained at 37°C in an atmosphere of 5% CO2 and 95% air.

Drug treatment, hypoxic incubation, and X-irradiation in vitro

Tumor cells were allowed to adhere to a 6-cm plastic dish and treated with 10 mM glycididazole or doranidazole before hypoxic incubation. To establish the hypoxic conditions (oxygen concentration ≤10 mmHg [1.3%]; unpublished data) for tumor cells, the dish was placed in a gas-exchangeable chamber and ultrapure N2 gas was continuously passed over the dish, which was placed on ice, for 25 min. The cells were then exposed to the indicated doses of X-rays while maintaining the gas flow. X-irradiation was performed with a Shimadzu PANTAK HF-350 X-ray generator (1.0 mm Al filter; 200 kVp; 20 mA; Shimadzu, Kyoto, Japan).

Clonogenic survival assay

At 5 h before hypoxic induction, 100–20,000 of SCCVII cells were seeded on a 6-cm plastic dish. After drug treatment, hypoxic induction, and X-irradiation as described above, the cells were incubated with fresh medium supplemented with 10% FBS under normoxia at 37°C for 8 days. The cells were subsequently fixed with methanol, stained with Giemsa solution, and scored under a microscope. Only colonies that contained more than 50 cells were scored as surviving cells. After the surviving fraction at each dose was calculated with respect to the plating efficiency of the non-irradiated control, the mean ± standard error of the surviving fractions obtained from three experiments was plotted. The survival curves were fitted to a linear-quadratic (LQ) model: SF=exp (−αDD2), where SF is the surviving fraction and D is the physical dose, by using the data analysis software Origin Pro 7 (OriginLab Co., Northampton, MA, USA).

Animal model

All animal experiments in this study were conducted according to the guidelines of the Law for The Care and Welfare of Animals in Japan and approved by the Animal Experiment Committee of the Graduate School of Veterinary Medicine, Hokkaido University. Male C3H/HeN mice were purchased from Japan SLC (Hamamatsu, Japan). SCCVII solid tumors were established via s.c. injection of 2×105 cells into the limbs of micle.

Drug treatment and X-irradiation in vivo

The experiment was initiated when the tumor volume (V=0.5 × length × width2) reached 250–450 mm3. The body weights measured before the experiments were in the range from 20–25 g. The animals were randomized into six groups of 9–10 animals per group: i) saline only; ii) saline and X-irradiation (30 Gy); iii) glycididazole only; iv) glycididazole and X-irradiation; v) doranidazole only; and vi) doranidazole and X-irradiation. Glycididazole and doranidazole were intravenously injected into mice at a dose of 200 mg/kg, 20 min before X-irradiation. For the irradiation of transplanted tumors, the mice were shielded with lead panels, except for the tumor-bearing limbs. X-irradiation was performed with an X-Rad iR-225 (1.0 mm Al + 0.5 mm Cu filters; 250 kVp; 16.7 mA; Precision X-Ray; North Branford, CT, USA) at a dose rate of 1.7 Gy/min. The tumor volume was measured three times per week and the tumor growth was monitored for a maximum of 47 days.

high performance liquid chromatography (HPLC) analysis

At 20 min after i.v. injection of the compounds, the mice were sacrificed and blood and tumor tissues were sampled. Serum was obtained via centrifugation of the blood sample at 5,000 × g for 15 min and passed through an Ultrafree-MC filtration device (EMD Millipore, Billerica, MA, USA). Tumor samples were homogenized with Polytron (Kinematica, Luzern, Switzerland) and centrifuged at 3,000 × g for 5 min. The supernatant was diluted with two volumes of methanol and centrifuged at 2,500 × g for 10 min. The obtained supernatant was mixed with two volumes of ethanol, which was subsequently evaporated completely. Aqueous serum and resolved tumor samples were analyzed using an HPLC system comprising a gradient pump (LC-10ADvp), an autosampler (SIL-10ADvp), an in-line degasser (DGU-20A3), a column oven (CTO-10ACvp), and a UV detector (SPD-10Avp) (all from Shimadzu). System control and data analysis were performed by using LCsolution (Shimadzu). Separation was performed by using a reversed phase column (4.6×250 mm) of TSK gel ODS-80Tm (TOSOH).

Statistical analysis

The Kaplan-Meier method was used to analyze the doubling times. Log-rank test was used to compare the doubling times between any 2 treatment groups.


Glycididazole radiosensitized cancer cells under hypoxic conditions to a similar extent as doranidazole did in vitro

To investigate the effects of glycididazole and doranidazole on the radiosensitivity of cancer cells, colony formation assay was performed. The clonogenic survival curves of SCCVII cells irradiated in vitro under normoxic and hypoxic conditions, with or without these drugs, are shown in Fig. 2A. In the absence of glycididazole, X-irradiation under hypoxia reduced the radiosensitivity of SCCVII cells. Under both normoxia and hypoxia without irradiation, 10 mM glycididazole was not toxic to SCCVII cells. The survival curves of SCCVII cells irradiated under normoxia show that glycididazole decreased the clonogenic ability. The dose that reduced cell survival to 10% (D10) obtained from the normoxic cell survival curve was 6.55 Gy, which decreased to 6.08 Gy when the cells were irradiated in the presence of glycididazole (Table I). The enhancement of radiation-inducing cell death was more pronounced in hypoxic condition; the D10 values were 9.18 and 7.09 in the absence and presence of glycididazole, respectively. The sensitizing enhancement ratio (SER) for glycididazole was 1.08 and 1.29 for normoxic and hypoxic conditions, respectively, which suggested that glycididazole sensitized both hypoxic and normoxic cells to radiation in vitro.

Table I.

Survival parameters and sensitizer enhancement ratios for SCCVII cells treated with X-irradiation combining with glycididazole or doranidazole.

Table I.

Survival parameters and sensitizer enhancement ratios for SCCVII cells treated with X-irradiation combining with glycididazole or doranidazole.

TreatmentOxygen conditionDrugα (Gy−1)β (Gy−2)D10 SERD10
Glycididazole   Normoxia0.1830.0266.551.08
Doranidazole   Normoxia0.1730.0316.291.02

[i] The biological parameters and sensitizer enhancement ratios (SER) were calculated based on survival curves. Calculation formula is shown in Materials and methods.

Alternatively, although 10 mM doranidazole exerted no sensitizing effect when combined with irradiation in aerobic conditions, a significant sensitizing activity was observed in combination with irradiation under hypoxic conditions (Fig. 2B). The SER for doranidazole, which was calculated from the D10 values in each condition, was 1.02 and 1.24 for normoxic and hypoxic conditions, respectively (Table I). These results suggested that glycididazole exerted a radiosensitizing effect on hypoxic cells that was comparable to that of doranidazole.

Glycididazole showed weak radiosensitizing effect on tumor growth compared with that of doranidazole in vivo

To evaluate the radiosensitizing effects of glycididazole and doranidazole on squamous carcinoma in vivo, SCCVII tumor-bearing mice were treated with 30 Gy X-irradiation 20 min after the i.v. administration of 200 mg/kg glycididazole or doranidazole. As shown in Fig. 3 and Table II, a single administration of either glycididazole or doranidazole exerted little effect on tumor growth. X-irradiated tumors exhibited delayed growth and the doubling time of tumor volume after X-irradiation was 18 days. The treatment with 200 mg/kg doranidazole significantly enhanced the inhibition of radiation-induced growth and extended the doubling time to 42 days (P<0.001). Although treatment with glycididazole at the same dose extended the doubling time to 20 days significantly (P<0.05), the enhancement rate was clearly smaller than that of doranidazole.

Table II.

Tumor doubling time.

Table II.

Tumor doubling time.

TreatmentDays (lower, upper limits)
Saline4 (4, 8)
Glycididazole4 (2, 6)
Doranidazole4 (4, 6)
Saline + X-rays18 (8, 20)
Glycididazole + X-rays20 (18, 33)a
Doranidazole + X-rays42 (27, 47)b,c

{ label (or @symbol) needed for fn[@id='tfn2-ol-0-0-7481'] } The median time required for tumor volume doubling is illustrated with lower and upper limits in parentheses. Statistical significance is indicated as

a P<0.05

b P<0.001, vs. Saline + X-rays

c P<0.01, vs. Glycididazole + X-rays.

Glycididazole was decomposed to metronidazole and its concentration was relatively low compared with that of doranidazole

To explain why glycididazole did not enhance radiation-induced tumor suppression, we assessed the chemical forms and tissue concentrations after the administration of glycididazole and doranidazole in vivo. The results of the HPLC analysis showed that the incorporated glycididazole was barely detected in its original form within the tumor and that the only detectable metabolite was metronidazole, as shown in Fig. 4A. In contrast, the administered doranidazole was detected as the undecomposed form (Fig. 4B). The concentrations of these drugs in the tumor and blood serum were also examined. As shown in Fig. 4C, the amount of glycididazole incorporated into tumor in the form of metronidazole was significantly lower (26.07±8.25 µg/g of tissue) than that of doranidazole (57.16±11.79 µg/g of tissue). This trend was also observed in blood serum.


The purpose of this study was to re-evaluate the radiosensitizing effect of glycididazole, which is widely used in China for clinical treatment, in vitro and in vivo. As shown in Fig. 2, treatment with 10 mM glycididazole improved the radiosensitivity of SCCVII cells under hypoxia, similar to doranidazole. Interestingly, the enhancement of radiation-induced cell death by glycididazole was observed even in normoxia. A recent report by Zeng et al demonstrated the similar effect of glycididazole on normoxic laryngeal cancer cells and revealed significant downregulation of ataxia-telangiectasia mutated (ATM), p-ATM, CHK2, and p53 and the upregulation of MDM2 and Cdk2 after the combined treatment with glycididazole and X-irradiation, not only in hypoxic conditions, but also in normoxic conditions, and concluded that glycididazole has the potential to inhibit the ATM signaling response after X-irradiation (20). Although glycididazole is composed of a metronidazole dimer, to the best of our knowledge, there are no reports to demonstrate that metronidazole exerted radiation modifying effects, except for its oxygen-mimetic properties owing to the electron affinity. Therefore, glycididazole may have unknown physiological activity and further investigation is necessary.

In contrast to the in vitro study that showed that the radiosensitizing effect of glycididazole (SER=1.29) was similar to that of doranidazole (SER=1.24) under hypoxic conditions, 200 mg/kg glycididazole exhibited a relatively weak sensitizing effect compared with that of doranidazole in SCCVII-transplanted tumor cells (Fig. 3). Only one study has examined the antitumor effect of glycididazole using the growth delay assay in a transplanted tumor model (20). The authors demonstrated the significant radiosensitizing potential of glycididazole in a xenografted Hep-2 tumor mouse model, but they employed a high dose of glycididazole (3×700 mg/m2/day). Combined with our results, glycididazole did not show as strong a radiosensitizing effect as expected from the in vitro study. The inconsistencies between the in vitro and in vivo studies may be explained by the results of the HPLC analysis (Fig. 4). In tumor lysate obtained 20 min after glycididazole administration, glycididazole was not detected in the HPLC spectra, but metronidazole was detected. These results suggested that the glycididazole incorporated into the tumor was rapidly decomposed and bound to biomolecules as metronidazole adducts. This hydrolysis is thought to occur in the presence of esterase or ester hydrolase. Mahfouz and Hassan examined the hydrolysis kinetics of a series of metronidazole amino acid ester prodrugs (21). In an aqueous phosphate solution of pH 7.4, the prodrugs exhibited adequate chemical stability (half-life, t1/2, 4–16 h). However, in 80% human plasma, the drugs were hydrolyzed to metronidazole within a few min. Metronidazole benzoate, an internal remedy, also underwent rapid hydrolysis; however, no significant hydrolysis of the ester in gastric fluid and intestinal fluid was observed, but only metronidazole was reported in the sera and urine of patients administered metronidazole benzoate (22,23). In addition, it was reported that a twin ester prodrug, which consisted of a dimer of metronidazole and twin esters, was chemically stable at the physiological pH buffer solution (t1/2, 13–40 h) but the release of metronidazole from the prodrug ensued rapidly in 80% human plasma (t1/2, 10–150 min) (24). These reports suggest that glycididazole, in which two metronidazoles are linked by the ester bond, can be easily decomposed to the parental form in vivo. Unfortunately, a high-dose amount of metronidazole is required to achieve radiosensitization; at this level, metronidazole causes severe nausea and vomiting (25). Therefore, to increase the bioavailability of glycididazole and to obtain a sufficient response in the tumor, it was necessary to increase its stability in blood through modification of the linker bond that connected the two metronidazoles. For example, the twin ester prodrug derived from phthalic acid is not a substrate for the enzyme esterase and shows a slow release of metronidazole (t1/2, 12.4 h) (24).

We think two advantages will be obtained if the stability of such a twin drug is improved as follows. First is that the availability of 2-nitroimidazole moiety for radiosensitization against hypoxic cells can be increased. Because 2-fold of 2-nitroimidazole moieties per mole are provided, the chance of oxidation of radiation-induced free radicals is thought to be increased, leading to the induction of much more cell killing. This effect may be more pronounced in a condensed microenvironment in vivo than a monolayer culture in vitro. Second, to establish the method to stabilize the linker bond that connected the two metronidazoles is important as a toehold to develop the stable polymeric nitroimidazole compounds. Thus far, few attempts to develop and evaluate the polymeric compounds have been achieved. The promising compounds with multiple 2-nitoroimidazole moieties have a potential not only to exhibit stronger radiation-enhancing effect as a hypoxic radiosensitizer, but also to accumulate in hypoxic region more efficiently as a hypoxic imaging probe.

In conclusion, glycididazole efficiently sensitized cancer cells to radiation under both hypoxia and normoxia in vitro. However, the expected extent of tumor regression could not be achieved by the combination of X-irradiation and glycididazole. The modification of the chemical structure to reduce the decomposition of glycididazole to metronidazole is necessary to improve the cure rate of the combined therapy with X-irradiation in clinic.


This study was partially supported by the JSPS KAKENHI, Japan [nos. 25861045 (H.Y.), 15K09983 (H.Y.), 26461875 (T.Y.) and 24659551 (O.I.)] and by the Takeda Science Foundation (H.Y.).



Harada H: How can we overcome tumor hypoxia in radiation therapy? J Radiat Res. 52:545–556. 2011. View Article : Google Scholar : PubMed/NCBI


Brown JM: Tumor hypoxia in cancer therapy. Methods Enzymol. 435:297–321. 2007.PubMed/NCBI


Horsman MR, Lindegaard JC, Grau C, Nordsmark M, Alsner J and Overgaard J: Chapter 3-dose-response modifiers in radiation therapy A2-gunderson, leonard LClinical radiation oncology. Tepper JE: 4th. Elsevier; Philadelphia, PA: pp. 51–62. 2016, View Article : Google Scholar : PubMed/NCBI


Kaanders JH, Bussink J and van der Kogel AJ: Clinical studies of hypoxia modification in radiotherapy. Semin Radiat Oncol. 14:233–240. 2004. View Article : Google Scholar : PubMed/NCBI


Overgaard J, Eriksen JG, Nordsmark M, Alsner J and Horsman MR; Danish Head and Neck Cancer Study Group, : Plasma osteopontin, hypoxia and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: Results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol. 6:757–764. 2005. View Article : Google Scholar : PubMed/NCBI


Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, Lindeløv B and Jørgensen K: A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother Oncol. 46:135–146. 1998. View Article : Google Scholar : PubMed/NCBI


Oya N, Shibamoto Y, Sasai K, Shibata T, Murata R, Takagi T, Iwai H, Suzuki T and Abe M: Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): Radiosensitization efficiency and toxicity. Int J Radiat Oncol Biol Phys. 33:119–127. 1995. View Article : Google Scholar : PubMed/NCBI


Shibamoto Y, Kubota T, Kishii K and Tsujitani M: Radiosensitivity of human pancreatic cancer cells in vitro and in vivo and the effect of a new hypoxic cell sensitizer, doranidazole. Radiother Oncol. 56:265–270. 2000. View Article : Google Scholar : PubMed/NCBI


Yahiro T, Masui S, Kubota N, Yamada K, Kobayashi A and Kishii K: Effects of hypoxic cell radiosensitizer doranidazole (PR-350) on the radioresponse of murine and human tumor cells in vitro and in vivo. J Radiat Res. 46:363–372. 2005. View Article : Google Scholar : PubMed/NCBI


Zhang L, Gong A, Ji J, Wu Y, Zhu X, Lv S, Lv H and Sun X: The radiosensitizing effect of doranidazole on human colorectal cancer cells exposed to high doses of irradiation. BMC cancer. 7:1882007. View Article : Google Scholar : PubMed/NCBI


Matsuoka H, Shibamoto Y, Kubota T, Tsujitani M and Majima T: In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas. Oncol Rep. 7:23–26. 2000.PubMed/NCBI


Murata R, Tsujitani M and Horsman MR: Enhanced local tumour control after single or fractionated radiation treatment using the hypoxic cell radiosensitizer doranidazole. Radiother Oncol. 87:331–338. 2008. View Article : Google Scholar : PubMed/NCBI


Yasui H, Asanuma T, Kino J, Yamamori T, Meike S, Nagane M, Kubota N, Kuwabara M and Inanami O: The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption. BMC Cancer. 13:1062013. View Article : Google Scholar : PubMed/NCBI


Nishimura Y, Nakagawa K, Takeda K, Tanaka M, Segawa Y, Tsujino K, Negoro S, Fuwa N, Hida T, Kawahara M, et al: Phase I/II trial of sequential chemoradiotherapy using a novel hypoxic cell radiosensitizer, doranidazole (PR-350), in patients with locally advanced non-small-cell lung Cancer (WJTOG-0002). Int J Radiat Oncol Biol Phys. 69:786–792. 2007. View Article : Google Scholar : PubMed/NCBI


Karasawa K, Sunamura M, Okamoto A, Nemoto K, Matsuno S, Nishimura Y and Shibamoto Y: Efficacy of novel hypoxic cell sensitiser doranidazole in the treatment of locally advanced pancreatic cancer: Long-term results of a placebo-controlled randomised study. Radiother Oncol. 87:326–330. 2008. View Article : Google Scholar : PubMed/NCBI


Sunamura M, Karasawa K, Okamoto A, Ogata Y, Nemoto K, Hosotani R, Nishimura Y, Matsui K and Matsuno S; PR-350 Study Group, : Phase III trial of radiosensitizer PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer. Pancreas. 28:330–334. 2004. View Article : Google Scholar : PubMed/NCBI


Zeng YC, Wu R, Xu ZG, Zhang XY, Fan GL, Wu LN, Wang YM, Hao SH, Zheng W, Chen XD, et al: Safety and radiation-enhancing effect of sodium glycididazole in locoregionally advanced laryngeal cancers previously treated with platinum-containing chemotherapy regimens: A preliminary report. Cancer Radiother. 14:59–64. 2010. View Article : Google Scholar : PubMed/NCBI


Li MY, Liu JQ, Chen DP, Qi B, Liang YY and Yin WJ: Glycididazole sodium combined with radiochemotherapy for locally advanced nasopharyngeal carcinoma. Asian Pac J Cancer Prev. 15:2641–2646. 2014. View Article : Google Scholar : PubMed/NCBI


Zeng YC, Wu R, Xing R, Chi F, Wang SL, Chen XD, Xuan Y, Wu LN, Duan QY, Tang MY, et al: Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study. Cancer Radiother. 20:187–192. 2016. View Article : Google Scholar : PubMed/NCBI


Zeng YC, Xing R, Zeng J, Xue M, Chi F, Xin Y, Fan GL, Wang HM, Duan QY, Sun YN, et al: Sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway. Tumour Biol. 37:5869–5878. 2016. View Article : Google Scholar : PubMed/NCBI


Mahfouz NM and Hassan MA: Synthesis, chemical and enzymatic hydrolysis and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility. J Pharm Pharmacol. 53:841–848. 2001. View Article : Google Scholar : PubMed/NCBI


Alestig K, Freij L and Arnold E: Absorption and excretion of metronidazole after administration of metronidazole benzoate mixture. Scand J Infect Dis. 12:149–152. 1980. View Article : Google Scholar : PubMed/NCBI


Mathew M, Das Gupta V and Bethea C: Stability of metronidazole benzoate in suspensions. J Clin Pharm Ther. 19:31–34. 1994. View Article : Google Scholar : PubMed/NCBI


Mahfouz NM, Aboul-Fadl T and Diab AK: Metronidazole twin ester prodrugs: Synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity. Eur J Med Chem. 33:675–683. 1998. View Article : Google Scholar


Urtasun R, Feldstein ML, Partington J, Tanasichuk H, Miller JD, Russell DB, Agboola O and Mielke B: Radiation and nitroimidazoles in supratentorial high grade gliomas: A second clinical trial. Br J Cancer. 46:101–108. 1982. View Article : Google Scholar : PubMed/NCBI

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Yasui, H., Kubota, N., Nishizumi, J., Sakai, Y., Yamamori, T., & Inanami, O. (2018). Preclinical study on hypoxic radiosensitizing effects of glycididazole in comparison with those of doranidazole in vitro and in vivo. Oncology Letters, 15, 1993-1998.
Yasui, H., Kubota, N., Nishizumi, J., Sakai, Y., Yamamori, T., Inanami, O."Preclinical study on hypoxic radiosensitizing effects of glycididazole in comparison with those of doranidazole in vitro and in vivo". Oncology Letters 15.2 (2018): 1993-1998.
Yasui, H., Kubota, N., Nishizumi, J., Sakai, Y., Yamamori, T., Inanami, O."Preclinical study on hypoxic radiosensitizing effects of glycididazole in comparison with those of doranidazole in vitro and in vivo". Oncology Letters 15, no. 2 (2018): 1993-1998.