In1 J Rodratron Oncology &ol Phys Vol. 20, PP. 1249-1254 Prmted in the U S A. All rights reserved.

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0360-3016/91 $3.00 + .OO 8 1991 Pergamon Press plc

??Original Contribution

A FLUORINATED 2-NITROIMIDAZOLE, KU-2285, HYPOXIC CELL RADIOSENSITIZER

AS A NEW

KEISUKE SASAI, M.D.,’ SEI-ICHI NISHIMOTO, PH.D.,* KAZUHIRO SHIMOKAWA, PH.D.,~ YORISATO HISANAGA, PH.D.,~ YOSHIZUMI KITAKABU, M.D.,’ YUTA SHIBAMOTO, M.D.,’ LIN ZHOU, M.Sc.,* JUN WANG, B.Sc.,* MASAJI TAKAHASHI, M.D.,4 TSUTOMU KAGIYA, PH.D.* AND MITSUYUKI ABE, M.D.’ ‘Department of Radiology, Faculty of Medicine, 2Department of Hydrocarbon Chemistry, Faculty of Engineering, 4Chest Disease Institute, Kyoto University, Kyoto 606; and 3Chemical Division, Daikin Industries, Ltd., Settsu 566, Japan To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, KU-2285 (a 2-nitroimidazole with an N’-substituent of CH2CF2CONHCH2CH,OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in viva radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were -0.96 V and -1.05 V vs Ag/Ag+ in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vim radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in viva-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H/ He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD,,, in %week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole. Hypoxic cell radiosensitizer,

2-nitroimidazole,

Fluorinated 2-nitroimidazole,

INTRODUCTION

hypoxic cell radiosensitizers (7, 19). Among the compounds hitherto synthesized, KU-2285 (a 2-nitroimidazole derivative bearing an N’-substituent group of CH2CF2CONHCH2CH20H) has seemed to be the most promising as a hypoxic cell radiosensitizer ( 19). In this study, the in vivo radiosensitizing activity and the acute toxicity of KU-2285 were compared with those of etanidazole to evaluate its clinical utility.

Misonidazole was the first hypoxic cell radiosensitizer that was extensively investigated clinically. However, the tolerable dose of this drug was limited because of the development of severe side effects, particularly an irreversible peripheral neuropathy, so that its potential effect as a sensitizer was not achievable (4, 20). Two types of 2-nitroimidazole derivatives, etanidazole and pimonidazole, are now being tested clinically. Because of less oral bioavailability caused by the decreased lipophilicity, etanidazole must be given intravenously to obtain sufficient concentration in plasma or tumor ( 1, 2 1). Pimonidazole shows a temporary central neurotoxicity rather than a peripheral neurotoxicity ( 11, 16); thereby, the maximum dose tolerated with a single injection was limited up to 0.75 g/m2. Recently, we used fluorine substitutions to the side chain of nitroazole compounds to develop several novel

METHODS

Kyoto

University,

AND MATERIALS

Compounds KU-2285 has the structure shown in Figure 1 and was developed by our group. Etanidazole was obtained from the National Cancer Institute (USA). For the in vivo radiosensitization experiments, both compounds were dissolved in physiological saline immediately before use.

Presented at the 3 1stAnnual Meeting of the American Society of Therapeutic Radiology and Oncology, San Francisco, CA, October 1-6, 1989. Reprint requests to: Keisuke Sasai, M.D., Department of Radiology, Faculty of Medicine, Kyoto 606, Japan.

KU-2285.

Supported in part by Grants-in-Aid from the Japanese MinEducation, Science and Culture (62010070, 63010070). Accepted for publication 14 December 1990.

istry of

Sakyo-ku,

1249

1250

1. J. Radiation Oncology 0 Biology0 Physics N

CT-JJI NO2

N

CH,CF, CONHCH,CH,OH Fig. 1. Structural formula of KU-2285

Using a method described previously (13, 15, 18, 19) the reduction potential (EyiD) of both compounds was measured relative to the Ag/AgCl (saturated)/35 mol dme3 KC1 electrode in Ar-purged N,N-dimethylformamide solution (0.01 mol dme3) containing 0.1 mol dmm3 tetra-N-butylammonium perchlorate as a supporting electrolyte. The octanol/water partition coefficients were measured in buffer at pH 7.4 according to the method of Fujita et al. (5). Animals In all the animal experiments, we used 8- or 9-weekold female C3H/He mice obtained from Japan SLC* or Clea Japan Inc.+ Sensitizer testing system Tumor radiosensitization. Tumor response was measured by an in vivo-in vitro assay (13, 15, 17) a growth delay assay, and a tumor control study, using the SCC VII tumor in C3H/He mice. SCC VII tumor cells were subcutaneously inoculated into both hind legs of mice for the in vivo-in vitro assay, or into the right hind leg only for the growth delay assay and the tumor control study in syngeneic 8- to 9-week-old female C3H/He mice. The growth delay assay also used a transplanted mammary tumor in its third transplant generation, which was subcutaneously inoculated into the right hind legs of C3H/ He mice (12). The cell yield in the in vivo-in vitro assay was 3.5 f 1.2 x lo7 cells/g (mean f S.D.), and the control plating efficiency was 36 f 10% (mean + S.D.). In the growth delay assay, tumor volume was estimated by caliper measurements on every day or alternate day of the three perpendicular diameters assuming an ellipsoid shape as previously described (12, 13, 15). In tumor control study, the tumors were checked for up to 120 days after irradiation. When the tumors grew to larger than 2 cm in diameter, the mice were sacrificed, and tumors were scored as uncured. In all assays using SCC VII tumor, the tumor was irradiated on reaching a volume of about 500 mm3. The SCC VII tumor had a hypoxic fraction of 5.4% under the

* Hamamatsu,

Japan.

June 199I, Volume 20, Number 6

conditions of the irradiation for the in vivo-in vitro assay and a fraction of 28% under those for the growth delay assay and control study (17). To obtain a growth curve for the transplanted mammary tumor, tumors were irradiated when they reached a volume of about 200 mm3. Radiosensitization of normal tissue. Mouse lethality within 30 days after irradiation (LD50,30) was used to evaluate the response of hematopoietic tissue. The microcolony assay (22) was used to evaluate the survival of epithelial cells of jejunal crypts. In the microcolony assay, mice were killed 3.5 days after irradiation and the jejunum was prepared for histological examination. Fifteen sections from five mice were used for each determination point. The number of regenerating crypts per circumference was counted. The number of surviving stem cells was calculated using the formula of Withers et al. (22). In both assays, 200 pg/g of etanidazole was injected intravenously 20 min before irradiation, or 200 pg/g of KU-2285 was given intraperitoneally 30 min before irradiation. Irradiation Irradiation was carried out using 10 MV X rays generated by a linear accelerator at a dose rate of 5.6 Gy/ min as described previously ( 12, 13, 15). For the in vivoin vitro assay, the LD50,30assay, and the microcolony assay, the mice received whole body irradiation. In the tumor control study and the growth delay assay, only the tumor-bearing leg was irradiated. Mice were not restrained for whole body irradiation, whereas they were fixed with adhesive tape with their limbs extended without anesthesia for local irradiation as described previously ( 17). Calculation of the sensitizer enhancement ratio (SER) The SER was calculated for a surviving fraction of 0.1% in the in vivo-in vitro assay (13, 15). In the growth delay assay for SCC VII tumor, the SER was calculated from the radiation dose at which it was necessary to get the same time to regrow to 4 times initial treatment volume with or without drug treatment, whereas for transplanted mammary tumors the SER was determined from the radiation dose that gave the same volume doubling time. In the tumor control study, the TCD50,,20 was calculated using probit analysis and the SER was determined from the ratio of the TCDS0,120values with or without drug treatment. Acute toxicity in mice The drug dose necessary to kill 50% of mice within seven days (LD50,7) was determined for both KU-2285 and etanidazole in 8-week-old female C3H/HeJ mice, using 30 mice for each compound. KU-2285 and etanidazole

+ Tokyo, Japan.

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A fluorinated 2-nitroimidazole, KU-2285 0 K. SASAI etal.

were dissolved in 0.5% Tween 80 solution to get the required concentration immediately before the examination of acute toxicity. RESULTS

Tumor radiosensitization In vivo-in vitro assay. For the time-course experiment, a single dose of 18 Gy was given at various time intervals after administration of 100 pg/g of KU-2285 or etanidazole (Fig. 2). The oral administration of etanidazole gave an inferior radiosensitizing effect, whereas there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. On the basis of these results, KU-2285 was administered intraperitoneally 30 min before irradiation, and etanidazole was given intravenously 20 min before irradiation in the SER experiments. Using the radiation survival curves (Fig. 3) SER’s were determined for KU-2285 at three different doses, as shown in Table 1. SER’s for etanidazole were also determined using the same method. The radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose. Growth delay assay. According to the results of the in vivo-in vitro assay, KU-2285 was given orally or intraperitoneally 30 min before irradiation, whereas etanidazole was administered intravenously 20 min before irradiation. Figure 4 shows dose-response curves for SCC VII tumor irradiated in the absence or in the presence of 100 Kg/g of KU-2285 or etanidazole. There was no significant difference in the radiosensitizing activity between oral KU2285 and intravenous etanidazole at the same dose.

0

18

21

Radiation

24

Dose

27

(Gy)

Fig. 3. Radiation dose survival curves for SCC VII tumors after a single dose irradiation with or without pretreatment of intraperitoneal administration of KU-2285 as determined by an in vivo-in vitro assay. Open diamond: 50 &g, open circle: 100 pg/ g, open triangle: 200 &g, closed diamond: without pretreatment.

Error bars are 1 SE. Figure 5 shows dose-response curves for transplanted mammary tumors in mice pretreated with intraperitoneal administration of 200 pg/g of KU-2285 30 min before irradiation or with intravenous injection of 200 pg/g of etanidazole 20 min before irradiation. There was no sig-

Table 1. Chemistry and sensitization data for KU-2285 and etanidazole Compound

??

6

W3

4

1

I

I

I

I

0

30

60

90

I

120

Time (mh) Fig. 2. The surviving fraction of the cells in SCC VII tumors after a dose of 18 Gy given to the tumors at different times after an administration of 100 /Is/s of KU-2285 or etanidazole. Closed star: without pretreatment, open triangle: KU2285 iv, open square: KU2285 ip, open circle: KU2285 orally, closed triangle: etanidazole iv, closed circle: etanidazole orally. Error bars are 1 S.E.

Molecular weight P* E ;,;nt SCC VII tumor SER (in vivo-in vitro)* 50 CLgig 100 pglg 200 @lg SER (regrowth delay)”

100 MlP SER (TCDXWO) 100 ccglg Transplanted mammary tumor SER (regrowth delay)** 100 rglg

Etanidazole

KU2285

214.2 0.040 -1.05

264.2 0.25 -0.96

1.18 1.28 1.43

1.24

1.31

1.35

1.40

1.55

1.43

1.55

1.34 1.45

* P: Partition coefficient in octanol/water. + EF$‘: Reduction potential vs. Ag/Ag+ in N,N-dimethylformide. * SER: Sensitizer enhancement ratio. 5 Calculated by the time for tumors to regrow to 4X initial treatment volume at 20 days. ** Calculated by the time for tumors to regrow to 2X initial treatment volume at 20 days.

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nificant difference found in the radiosensitizing effects of the two compounds.

ioi , , , , i= 20 10 Radiation dose

0

30 (Gy)

40

Fig. 4. Dose response curves of SCC VII tumors, that is, time to regrow 4X initial treatment volume as a function of radiation dose. Error bars are 1 S.E. from more than eight mice. Open circle: 100 rg/g KU-2285 administered orally, closed circle: 100 &g etanidazole injected intravenously, open triangle: without pretreatment before irradiation.

Tumor control study The effects of irradiation alone, irradiation 20 min after the intravenous injection of 100 pg/g of etanidazole, and irradiation 30 min after the intraperitoneal injection of 100 pg/g of KU-2285 are summarized in Figure 6. The percentage of tumors judged to be cured 120 days after treatment was plotted as a function of the radiation dose given. The TCD50,,zo of control tumors which received irradiation without pretreatment was 79.0 Gy with a 95% confidence interval of 72.6-85.9 Gy as calculated by probit analysis. Pretreatment of tumor-bearing mice with KU2285 significantly enhanced tumor radiosensitivity, as indicated by a reduction in the TCD50,,20 to 5 1.O Gy with a 95% confidence interval of 47.3-55.0 Gy. In the case of etanidazole, the TCD50,120was 56.0 Gy, with a 95% confidence interval of 50.7-6 1.8 Gy. Radiosensitization of normal tissue The LD50,30calculated by probit analysis was 7.6 Gy with a 95% confidence interval of 7.3-8.0 Gy for mice without pretreatment, 7.8 Gy with a 95% confidence interval of 7.6-8.0 Gy for mice pretreated with 200 pug/gof etanidazole, and a 7.5 Gy with 95% confidence interval of 7.2-7.8 Gy for mice pretreated with 200 pg/g of KU2285. The dose-survival data obtained from the microcolony assay for mice without pretreatment, mice pretreated with 200 pg/g of etanidazole, and mice pretreated with 200 pg/g of KU-2285 are shown in Figure 7. Neither etanidazole nor KU-2285 significantly affected the response of normal tissue to irradiation. Acute toxicity The acute toxicity measured as the LDSO,, was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy)

0

10 Radiation

20 Dose

30

40

(Gy)

zo

/--+y-

0

40

50

60

Radiation Fig. 5. Dose response curves of transplanted mammary tumors, that is, volume doubling time as a function of radiation dose. Error bars are 1 S.E. from more than eight mice. Closed triangle:

200 rgfg KU-2285 administered intraperitoneally, open triangle: 200 pg/g etanidazole injected intravenously, closed diamond: without pretreatment before irradiation.

70

60

Dose

90

100

(Gy)

Fig. 6. Probability of SCC VII tumors locally controlled 120 days after a single dose irradiation. Open circle: 100 pg/g KU2285 administered intraperitoneally, closed circle: 100 pg/g etanidazole intravenously, open triangle: without pretreatment before irradiation. Bars indicate 95% confidence intervals.

A fluorinated 24troimidazole,

I



-kII 0

9 Radiation

12 Dose

15 (Gy)

Fig. 7. Survival ofjejunal stem cells per circumference ofjejunum following irradiation. Mice were irradiated without pretreatment (open triangle), with pretreatment of intraperitoneal administration of 200 pg/g KU-2285 (open circle), or with pretreatment of intravenous administration of 200 pg/g etanidazole (closed circle). Bars are 1 SD. from 15 sections.

and 4.25 g/kg (orally) for KU-2285, and 4.75 g/kg (intravenously) for etanidazole (Table 1). DISCUSSION Several fluorine-incorporated 2-nitroimidazole derivatives have been synthesized, mainly with the goal of obtaining probes for the identification of hypoxic cells by 19F magnetic resonance spectroscopy or 18F positron emission computerized tomography (6, 8- 10). Recently, we have incorporated fluorine atoms into the side chain of 2-nitroimidazole, 3-nitro- 1,2,4-triazole, and 4-nitro- 1,2,3-triazole derivatives to modify their tumor affinity and thereby their radiosensitizing activity (7, 19). There are several related compounds that are highly active but too toxic to use in the clinic. We also developed a novel fluorine-modified 2-nitroimidazole derivative, KU2285, which showed potent radiosensitizing activity in an in vitro and in vivo screening system for hypoxic cell radiosensitizers using EMT6/KU cells, and low acute toxicity in ICR mice. In the in vitro study, the SER at 1 mmol dmP3 of KU-2285 was 1.6, whereas it was 1.5 for etanidazole. In the in vivo study, the drug dose to achieve an SER of 1.5 was 1 IO pg/g for KU-2285, whereas it was 170 pg/g for etanidazole ( 19). In the studies presented here, KU-2285 was reconfirmed

KU-2285 0 K. SASAI etal.

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to show a good radiosensitizing activity for two different tumors. Even the oral administration of KU-2285 significantly sensitized the SCC VII tumor to irradiation as well as intravenous or intraperitoneal administration. This correlates with the observation that the concentration of KU-2285 in both plasma and SCC VII tumor were similar when KU-2285 was given orally, intravenously, or intraperitoneally (Wang J., 1989, unpublished data). Although the acute toxicity of KU-2285 as measured by the LD50,7 was twice that of intravenous etanidazole when it was injected intravenously or intraperitoneally, it was almost equal to that of etanidazole when administered orally. Furthermore, note that the main dose limiting factor of 2-nitroimidazoles in the clinic is not acute toxicity but chronic peripheral neurotoxicity (2, 3). We have previously demonstrated that the drug exposure to the murine peripheral nervous tissue was a useful indicator of the chronic peripheral neurotoxicity of various 2-nitroimidazoles in the clinic (14). Although the drug exposure to murine peripheral nerves as measured by AUC (area under the concentration-time curve) from time 0 to 240 min was similar for KU-2285 and etanidazole (14), the biological half-life of KU-2285 in the peripheral nervous tissue was shorter than that of etanidazole (14). Therefore, it would be expected that the incidence of chronic peripheral neurotoxicity in the clinic of this new compound, KU-2285, would be lower than or similar to that of etanidazole. However, it is possible that the higher levels of KU-2285 in brain relative to etanidazole may mean that this agent could be more toxic to the central nervous system. Although its side chain is similar to that of etanidazole, KU-2285 has a much higher octanol/water partition coefficient than etanidazole, and is similar in this respect to misonidazole. Thus, incorporation of a -CF,structure into the side chain group of -CH2CONHCH2CH20H, borne by etanidazole has made the compound more lipophilic. Because of its higher lipophilicity, the concentration of KU-2285 in murine brain was a little higher than that of etanidazole (14). As shown in Figure 2, KU2285 showed a good radiosensitizing activity even when administered orally, whereas the oral administration of etanidazole was not effective against the SCC VII tumor. This difference was probably also related to the difference in lipophilicity between these two 2-nitroimidazole derivatives. KU-2285 has a pair of fluorine atoms in its side chain, and should be useable not only as a hypoxic cell radiosensitizer but also as a probe for hypoxic cells when performing 19Fmagnetic resonance spectroscopy or t8F positron emission computerized tomography. CONCLUSION 1. The in vivo radiosensitizing activity of KU-2285 was similar to that of etanidazole at the same administration dose.

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2. The advantage of KU-2285 over etanidazole is that its oral administration still had a good radiosensitizing effect on SCC VII tumors.

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3. The acute toxicity of KU-2285 when given orally was similar to that of etanidazole administered intravenously.

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Fluosol-DA. Int. J. Radiat. Oncol. Biol. Phys. 16: 1149-l 152; 1989. Sasai, K.; Shibamoto, Y.; Takahashi, M.; Abe, M.; Wang, J.; Zhou, L.; Nishimoto, S.; Kagiya, T. A new, potent 2nitroimidazole nucleoside hypoxic cell radiosensitizer, RP170. Jpn. J. Cancer Res. 80:1113-1118; 1989. Sasai, K.; Shibamoto, Y.; Takahashi, M.; Ito, T.; Nishimoto, S.; Abe, M. Pharmacokinetics of 2-nitroimidazole hypoxic cell radiosensitizers in rodent peripheral nervous tissue. Int. J. Radiat. Oncol. 57:971-980; 1990. Sasai, K.; Shibamoto, Y.; Takahashi, M.; Zhou, L.; Hori, H.; Nagasawa, H.; Shibata, T.; Inayama, S.; Abe, M. KIH802, an acetohydroxamic acid derivative of 2-nitroimidazole, as a new potent hypoxic cell radiosensitizer: radiosensitizing activity, acute toxicity and pharmacokinetics. Cancer Chemother. Pharmacol. 26: 112- 116; 1990. Saunders, M. I.; Anderson, P. J.; Bennett, M. H.; Dische, S.; Minchinton, A.; Stratford, M. R. L.; Tothill, M. The clinical testing of Ro-03-8799-pharmacokinetics, toxicology, tissue and tumor concentrations. Int. J. Radiat. Oncol. Biol. Phys. 10:1759-1763; 1984. Shibamoto, Y.; Sasai, K.; Abe, M. The radiation response of SCC VII tumor cells in C3H/He mice varies with the irradiation condition. Radiat. Res. 109:352-354; 1987. Shibamoto, Y.; Nishimoto, S.; Mi, F.; Sasai, K.; Kagiya, T.; Abe, M. Evaluation of various types of new hypoxic cell sensitizers using the EMT6 single cell-spheroid-solid tumour system. Int. J. Radiat. Biol. 52:347-357; 1987. Shibamoto, Y.; Nishimoto, S.; Shimokawa, K.; Hisanaga, Y.; Zhou, L.; Wang, J.; Sasai, K.; Takahashi, M.; Abe, M.; Kagiya, T. Characteristics of fluorinated nitroazoles as hypoxic cell radiosensitizers. Int. J. Radiat. Oncol. Biol. Phys. 16:1045-1048; 1989. Wasserman, T. H.; Phillips, T. L.; Johnson, R. J.; Gomer, C. J.; Lawrence, G. A.; Sadee, W.; Marques, R. A.; Levin, V. A.; VanRaalte, G. Initial United States clinical and pharmacologic evaluation of misonidazole (Ro-07-0582), a hypoxic cell radiosensitizer. Int. J. Radiat. Oncol. Biol. Phys. 51775-786; 1979. White, R. A. S.; Workman, P.; Brown, J. M. The pharmacokinetics and tumor and neural tissue penetrating properties of SR-2508 and SR-2555 in the dog-hydrophilic radiosensitizers potentially less toxic than misonidazole. Radiat. Res. 84:542-561; 1980. Withers, H. R.; Elkind, M. M. Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int. J. Radiat. Biol. 17:261-267; 1970.

A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.

To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, ...
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