3—［（4—amino−2—methyl−5—pyrimidinyl）—methyl］−1—（2—chloroethyl）−1—nitrosourea （ACNU）の生体内代謝に及ぼすphenobarbitalの作用

THE EFFECT OF PHENOBARBITAL ON THE METABOLISM OF 3-[(4-AMINO-2-METHYL-5-PYRIMIDINYL)-METHYL]-1-(2-CHLOROETHYL)-1-NITROSOUREA (ACNU) IN VIVO

　抄録　Phenobarbital （PB）は，肝マイクロソームの酵素誘導を介して各種薬剤の生体内代謝に変化をもたらすことが知られている。我々は，悪性脳腫瘍の治療で繁用されるニトロソウレア系抗癌剤−3—［（4—amlno−2—methyl−5—pyrimidinyl）—methyl］−1-2—chloroethyl）−1—nitrosourea （ACNU）の生体内代謝に及ぼすPBの作用を，主にsodium valproate （SV）と比較しつつ検討した。PB 19 mg／kg／day （i．m），38 mglkg／day （i．m）で4日間前処置をしたラット群では，　ACNUのほぼLD₅₀に当たる47 mg／kg （i．　v）による急性毒性の発現が無処置群に比較して有意（P＜0.005）に減少したが，SVおよびphenytoinには同様の効果を認めなかった。PB 19 mg／kglday （i．m）で4日間前処置をしたRG 12移植CD FisherラットではACNU 20 mg／kg （i．v）の抗腫瘍効果が，無処置群およびSV前処置群に比較して有意（P＜0.001, P＜0.05）に低下した。PB 19 mg／kg裕day （i．　m）および38 mg／kg／day （i．　m）で4日間前処置をした担脳腫瘍CDFisherラットにACNUの大量−40mg／kg／day （i．v）および60 mg／kglday （i．　v）を投与しても延命効果は得られず，PB併用によるACNU経静脈大量療法の可能性は悲観的と考えられた。しかし，PB併用によるACNUの頸動脈内大量投与は，その毒性を抑えつつ抗腫瘍効果を高め得る可能性があり，今後検討を要すると考えられた。

The nitrosourea compounds are often used in the treatment of patients with malignant brain tumors in combination with anticonvulsants, such as phenobarbital (PB). Since PB can induce hepa-tic microsomal enzyme-P 450 and degrade nitro-soureas in vivo, the effect of PB on tumoricidal activity in relation to toxicity of 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1- (2-chloroethyl)-1-nitrosourea (ACNU) was studied using a rat brain tumor model.

To determine toxicity, CD-Fisher rats were treated for 4 days with 19 and 38 mg/kg/day of PB (i. m), 0. 4 and 0. 7 g/kg/day of sodium valpro-ate-SV (p. o), or 3 days with 50 mg/kg of pheny-toin (i. v) prior to an administration of 47 mg/kg of ACNU (i. p). The mortality rate by the toxi-city within 14 days after administration of ACNU was calculated in each group. The toxicity of ACNU was markedly reduced in PB pretreated rats compared with those without pretreatment or treated with SV or phenytoin. The tumoricidal activity of ACNU was evaluated in CD-Fisher rats with RG 12 brain tumors. Rats received 20 mg/kg ACNU after pretreatment with 19 mg/kg/ day of PB (i. m) or 0.2 g/kg/day of SV (p. o) for 4 days. The mean survival days and the percen-tage increase in life span (%ILS) were compared in each group. Pretreatment with PB significantly reduced the tumoricidal activity of ACNU as compared with control without pretreatment (p< 0.001) or pretreatment with SV (p<O.05). Admi-nistration of higher dose of ACNU (40 mg/kg or 60 mg/kg) to tumor bearing rats pretreated with 19 or 38 mg/kg/day of PB for 4 days also did not show any increase of %ILS. Those results sugges-ted that higher dose of ACNU can be adminis-tered to the rats pretreated with PB without any significant increase of tuoricidal activity. Further studies will be necessary to elucidate the possibi-lity that intraarterial administration of ACNU combined with PB pretreatment may increase tumoricidal activity.