表在性膀胱癌に対しanthramycin系に属する抗癌性抗生物質Neothramycin (NTM)を使用した.NTMの膀胱内注入療法で用いた投与量は以下のごとくである.初回にはNTM 10 mgを滅菌蒸留水20 mlに溶解させて膀胱内に注入し, 副作用がないため40 mgに増量した.投与間隔は2週に1回からはじめ, 1日2回の膀胱内注入を行なった.最近の2例に膀胱内注入療法に加えてNTM 20 mgの経静脈性全身投与の併用療法を試みた.成績は11例中著効4例, 50%以上の縮小を認めた有効6例で, 無効1例であった.副作用としては3症例に一過性の膀胱刺激症状を認めたNeothramycin (NTM), an anthramycin-group anticancer antibiotic, was used in the treatment of superficial carcinoma of the bladder. NTM was instilled into the bladder in the following dosages. Ten mg NTM in 20 ml of sterile distilled water was given first, and increased to 40 mg in 20 ml. This procedure was performed every second week to twice a day. Recently, in 2 patients, the treatment has been combined with 20 mg NTM intravenous administration. In 4 of the 11 patients (36%) the tumors disappeared completely, while in 6 patients (55%) there was partial disappearance of more than 50% and in one patient (9%) there was no effect. Three of the patients had irritable bladder symptom (temporarily). NTM was concluded to be effective for superficial carcinoma of the bladder

HACHISUKA, Yusuke

HIRAO, Noriaki

IWASE, Yutaka

SAKAGAMI, Hiroshi

TSUGAYA, Masayuki

WASHIDA, Hiroto

Kyoto University Research Information Repository

Title The treatment of bladder cancer by neothramycinAuthor(s)TSUGAYA, Masayuki; WASHIDA, Hiroto; HIRAO, Noriaki;HACHISUKA, Yusuke; SAKAGAMI, Hiroshi; IWASE,YutakaCitation泌尿器科紀要 (1986), 32(10): 1443-1448Issue Date1986-10URL http://hdl.handle.net/2433/118943RightType Departmental Bulletin PaperTextversionpublisherKyoto University1443 [Acta Urol. Jpn. Vol. 32 ] No. 10, October 1986 THE TREATMENT OF BLADDER CANCER BY NEOTHRAMYCIN Masayuki TSUGAYA, Hiroto WASHIDA, Noriaki HIRAO, Yusuke HAcHIsuKA, Hiroshi SAKAGAMI and Yutaka IWASE From the Department of Urology. Anjo Kosei Hospital (Chief: Dr. H. Washida) Neothramycin (NTM), an anthramycin-group anticancer antibiotic, was used in the treat-ment of superficial carcinoma of the bladder. NTM was instilled into the bladder in the following dosages. Ten mg NTM in 20 ml of sterile distilled water was given first, and increased to 40 mg in 2') ml. This procedure was performed every second week to twice a day. Recently, in 2 p"tients. the treatment has been combined with 20 mg NTM intravenous administration. In 4 of the II patients (36%) the tumors disappeared completely, while in 6 patientg (55 %) there was partial di.appearance of more than 50% and in one patient (9%) there was no effect. Three of the patients had irritable bladder symptom (temporarily). NTM was concluded to be effective for superftcial carcinoma of the bladder. Key words: Superficial bladder cancer, Intravesical chemotherapy, Neothramycin Since the treatment of intravesical in-stillation of thio-TEPA by Jones and SwinneyD, the method of topical che-motherapy with several anti-cancer drugs for superficial bladder cancer have been reported and it is now an established me-thod of anti-bladder cancer treatment. This paper presents a summary of the first experience in the treatment of blad-der cancer by the intravesical instillation of neothramycin. Neothramycin, abbre-viated NTM, is a new anti-cancer anti-biotic that was isolated from the culture broth of streptomyces strain MC 916-C4-HO~~ 11J~11H 1 CH3 0 7 5 N 6 4 3 o h 2 R2 R, by Umezawa et a1.2,3). It is structur-ally similar to anthramycin, sibiromycin, tomaymycin etc. of the anthramycin group. The antibiotic contains almost equal amounts of neothramycin A andB. The molecular weight of NTM is 262.1 (Fig. 1). DNA has been reported to be the chemoreceptor of NTM and its re-action rate to be slower than that of other DNA-binding antibiotics, including an-thramycin, tomaymycin, sibiromycin, adriamycin and actinomycin4 ,S). NTM inhibits biosynthesis of nucleic acid, particularly RNA synthesis at the cellular NTM A: R, =OH. R2 =H NTM B:R,=H. R2=OH Neothramycin A : (3 S. 1 faS)- 2. 3, 5, , 1 a-tetra hydro- 3, 8 -dihydroxy- 7-methoxy- 5 -oxo- 1 H-pyrrolo[ 2, 1 -c] [ 1 , 4] benzodiazepine Neothramycin B : (3 R, 11 as)- 2, 3, 5,11 a-tetrahydro- 3, 8 -dihydroxy- 7-metho*y- 5 -oxo-l H-pyrrolo [2, 1 -c] [ 1 , 4] benzQdiazepine Molecular weight: 262.1. Fig. I. Chemical structure of Neothramycin (NTM) 1444 Acta Urol. Jpn. Vol. 32. No. 10, 1986 leveI4 ,5) • MATERIALS AND METHODS This study comprised 9 men and 2 wo-men with superficial bladder cancer. The patients were between 55 and 87 years Table 1. Clinical data of 11 patients Age (yrs) : Range 55-87 Av. 72.7 Sex: M 9 F 2 Grade of differentiation Grade I 5 Grade n 6 Table 2. Regimen of this study Dose of NTM Interval of insti Iistion 10111i- Weekly (1 IW) 20111i- Daily ( 1 10) 40mg. 4Omg. Twice. week. weekly (2-1/1-2w) or every other week Daily or 6 times a week (!/D) 6'W 40mg. Twice a day (2/0) !if. *: The same cases Cases 1· 3** 6* 2 old, with a mean of 72.7 years old. Tumor classification was performed with the aid of urethrocystoscopy, ultrasonography, cytologic evaluation of urine and histo-logic study of transurethrally obtained biopsy specimens. Five patients had grade 1 tumors and 6 patients had grade 2 tumors without evidence of invasion (pTa-pTlb). The tumors were smaller than a walnut (Table I). The instillation was first carried out with 10 mg of NTM in 20 ml sterile water once a week. As some favourable effects were observed in the examination of cystoscopy after the first course, the doses of NTM were increased up to 40 mg in 20 ml sterile water. This procedure was performed from twice a day to every other week (Table 2). The absorption of NTM from the blad-der mucosa was studied in 3 patients. The NTM solution which was prepared to make a concentration of 40 mg NTM per 20 ml was instilled for one hour by means of an indwelling catheter. RESULTS Table 3 shows the results. In 4 of the 11 patients (36%), the tumors disappeared completely, while in 6 patients (55%) there was partial disappearance, and in one patient (9%) there was no effect. The response rate was 91 percent. Table 3. Clinical data and results of treatment Grade of Single or Dose of NTM Cases Age Sex Size (Interval of instillation) Result Side effect differentiation multiple [intravenous administration) 1- K.V. 71 M Gl Thumb's head S 4OmgX21 (2/0) CR Frequency 2, M.K. n M G2 Thumb's head M 40mgX21 (210) CR Frequency 3, V.H. 75 F Gl Little·finger's S 4OmgX12 (6 /W) CR heed (20mgX 7) 4. K.N. 56 M G2 Thumb's head M 4OmgX26 (6 IW) CR (20mgX 9) 5, K.K. 61 M G2 Walnut large S 4OmgX14 (110) PR 6, G.N. 84 M Gl Walnut large S 40mgX 6 (110) PR 7, M.I. 87 M G2 Thumb's head S 4OmgX24 (6/W) PR 8, M.M. 76 F G2 Bean large S 20mgXl0 (110) PR 9, E.E. 55 M Gl Rice large M 10mgX 9 (1/Wl PR 40mgX21 (1/2W-2-3/W) 10. U.V. 80 M G2 Little-finger's M 401IIgXl0(1 /1- 2W) PR Frequency h.ad 40mgX18 (6/w) 11. K.O. 78 M Gl Pea large M 40lllgXl0 (l-2!W) NC Tsugaya et al: Bladder cancer Neothramycin 1445 Table 4. No recurrence Recurrence ng/m' 75 50 25 Recurrence after treatment Result of Treatment CR P R NC with TUR without TUR 2 2 3 2 O~--~--~2~--~3~--~4~--~5----~6 Hours Fig. 2. Serum concentration of NTM after absorption from bladder cavity Two of the 4 patients who became tu-mor-free were treated by intravesical NTM 40 mg twice a day, and the others treated by intravesical NTM 40 mg 6 ti-mes a week combined with intravenous administration of NTM 20 mg (Table 3). Three patients experienced irritable blad-der symptoms temporarily. In 2 of them, the increasing frequency occurred dur-ing treatment which was performed twice a day, and in the other the increasing fre-quency occurred during treatment which was performed 6 times a week (Table 3). Two of the 4 patients who became tumor-free were still without recurrence after 6 and 9 months, respectively. In the others, recurrences occurred after 2 and 4.5 months, respectively. In 4 of the 6 patients whose tumors were reduced 50 % or more, TUR was performed after this treatment. In one of this group there was no recurrence after 16 months, but in 5 of these patients recurrences appeared after 2.5 to 7 months (mean of 4.4) (Table 4). Absorption studies were carried out in 3 patients at a concentration of 40 mg NTM per 20 ml The maximum serum concentration of NTM was 74.9 ngjml, 69.9 ngjml in 2 patients, respectively and less than 25 ngjml in the other patient (Fig. 2). CASE REPORTS Case I; A 76-year-old woman was ad-mitted to our hospital with gross hema-turia. Cystoscopic examination revealed papillary tumor in the right lateral wall. Bladder biopsy revealed transitional cell carcinoma of grade 2. Intravesical instil-lation of NTM, 20 mg dissolved in 20 ml sterile distilled water was given daily for 10 days. Fig. 3 shows the cystoscopical findings before and after treatment. The tumor was reduced to approximately half after treatment. Ultrasonographic view of the lower abdomen showed the tumor, measuring 13 mm in height by 13 mm in diameter before treatment, and measuring 7 mm in height by 8 mm in diameter after treat-ment (Fig. 4). Case 2; A 71-year-old man was hospi-talized because of gross hematuria and Fig. 3. Cystoscopical findings before and after treatment in Case I 1446 ACla Urol. Jpn. Vol. 32, No. 10, 1986 Fig. 4. Ultrasonographic views before and after treatment in Case I Fig. 5. C.,.stoscopical findings before and after treatment in Case 2 Fig. 6. Ultrasonographic views before and after treatment in Case 2 frequency. Cystoscopy revealed papillary tumor in the right lateral wall. Bladder biopsy revealed transitional cell carcinoma of grade 2. Intravesical instillation of NTM 40 mg in 20 ml sterile water was given twice a day for 21 times. Fig. 5 shows the cystoscopical findings before and after treatment the tumor has disappeared after treatment. Ultrasonographic view demonstrated a large tumor, measuring 21 mm in height by 31 mm in diameter before treatment. The tumor has disappeared after treat-ment (Fig. 6). DISCUSSION Intravesical Thio-TEPA was first used to treat bladder cancer in 1961. Although intravesical Thio-TEPA was found to be effective, serious effects, chiefly myelosup-pression, hindered its clinical application. The molecular weight of Thio-TEPA may be related inversely to the absorption rate. Yeates reported that molecular size determined absorption from the bladder and the substances absorbed from the bladder have molecular weights of under 200]) The molecular weight of Thio-TEPA is 189 and it should, therefore, be absorbed6) The molecular weight of NTM is 262. 1 and, therefore, it should not be absorbed. However, there is a little absorption of NTM from the blad-der mucosa. Absorption studies were carried out in 3 patients at a concentra-tion of 40 mg NTM per 20 ml of sterile water. The NTM solution was then in-stilled for one hour by means of an in-dwelling catheter. More than 74.9 ng/ml NTM was not found in the blood of 3 patients. When NTM was administered intrave-nously, gastro-intestinal disturbance such as nausea and vomiting were the most frequen t ad verse reactions 7). There was no severe toxicity to the liver, kidney, heart or central nervous system. There was, therefore, no systemic side effects due to absorption of NTM7). When NTM was administered intrave-nously in rabbits, the highest levels were shown in the kidney and urinary bladder, which might have been due to urinary excretionS). We had experienced that the size of supraclavicular lymphonodi metastasis of bladder tumor was decreased by administration of NTM intravenously. Therefore, the effect of combined NTM given intravesically and intravenously was expected to be excellent compared with instillation alone. Complete regresslOn Tsugaya et al : Bladder cancer. Neothramycin 1447 was observed with the combination therapy in 2 patients. Three of the 11 patients had irritable bladder symptoms during treatment. All recovered, however, and bladder capacity gradually normalized one or two months after the instillation ceased. The absence of systemic and severe local side effects is an advantage in treatment with NTM. In the present study there was recur-rence of bladder tumor in 2 of 4 patients who became tumor-free and in 3 of the 4 patients who had partial regression after treatment as an adjuvant to transurethral resection. Our limited experience does not permit definite conclusions concerning the tumor-prophylactic effect of intrave-sical NTM, but NTM seems to have little value as a prophylactic agent to prevent recurrences of bladder cancer. It is clear from our series of patients that NTM is at least as safe and effective as any other drugs which have been tried. We reported a summary of this paper at the 6th Congress of European Associa-tion of Urology 1984. REFERENCE 1) Jones HC and Swinney J : Thio-TEPA in the treatment of tumors of the bladder. Lancet 2: 615~6r:l, 1961 2) Takeuchi T, Miyamoto M, Ishizuka M, Naganawa H, Kondo S, Hamada M and Umezawa H: Neothramycins A and B, new antibiotics. J Antibiotics 24: 93~96, 1976 3) Miyamoto M, Kondo S, Naganawa H, Ma-eda K, Ohno M and Umezawa H: Structure and synthesis of Neothramycin. J Antibio-tics 30: 340~343, 1977 4) Maruyama IN, Suzuki H and Tanaka N: Mechanism of action of Neothramycin. 1. The effect on macromolecular synthesis. J Antibiotics 31: 761~768, 1978 5) Maruyama IN, Tanaka N, Kondo Sand Ume-zawa H : Mechanism of action of Neothra-mycin. 2. Interaction with DNA. J Anti-biotics 32: 928~934, 1979 6) Lunglmayr G and Czech K : Absorption studies on intr:tluninal Thio-TEPA for to-pical cytostatic treatment of low-stage blad-der tumors. J Urol 106: 72~H, 1971 7) Kimura K and Ogawa M: Phase 1 trial of a new antitumor antibiotic, Neothramycin : A cooperative study group of Neothramycin Study. Cancer Treatment Symposia 1 : 75 ~78, 1983 8) Fujita H, Ogawa K, Okada A, Kusama T, Kajii K, Suga S and Kimura K: Pharma-cokinetics of Neothramycin in animals and man. J Antibiotics 35: 1093~1l00, 1982 (Accepted for publication, November 20, 1985) 1448 ActaUroLJPn。Vol.32,No.10,1986和文抄録Neothramycinによる膀胱癌の治療安城更生病院泌尿器科(部長:和志田裕人)津ケ谷 正 行*・ 和志田 裕 人平 尾 憲 昭*・蜂須賀 祐 介*阪 上 洋 ・ 岩 瀬 豊表在性膀胱癌に対しanthramycin系に属する抗癌性抗生物質Neothramycin(NTM)を使用した.NTMの 膀胱内注入療法で用いた投与量は以下のごとくである.初 回に はNTM10mgを 滅菌蒸留水20mlに溶解させて膀胱内に注入 し,副作用がないため40mgに 増量した.投与間隔は2週 に1回 からはじめ,1日2回 の膀胱内注入を行なった.最近の2例*現:名古屋市立大学医学部泌尿器科学教室に膀胱内注入療法に加えてNTM20mgの 経静脈性全身投与の併用療法を試みた.成績は11例中著効4例(36%),50%以上の縮小が認められた有効6例(55%)で,無効1例(9%)であった.副 作用としては3症例に一過性の膀胱刺激症状が認められた.表在性膀胱癌の治療にはNTMが 有効な薬剤であると考えられる.

Neothramycinによる膀胱癌の治療

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Neothramycinによる膀胱癌の治療

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