ヌードマウス継代移植ヒト膀胱癌を用いたcis-Diamminedichloroplatinum(2)を主剤とする非交差耐性同調多剤併用化学療法の研究

Abstract

Vincristine (VCR), peplomycin (PEP), methotrexate (MTX), cis-diamminedichloroplatinum(2) (CDDP), cytosine arabinoside (Ara-C), 5-fluorouracil (5-FU)の6剤併用化学療法を考案し, BT-8株およびBT-11株のヌードマウス継代移植ヒト膀胱癌を用いてその効果を検討した.1)直接抗腫瘍効果では, BT-8株おいて, CDDP (2.5 mg/kg/day×6), ADM (adriamycin: 3 mg/kg/day×6), CPM (cyclophosphamide: 10 mg/kg/day×10)の単剤投与群は, それぞれに有効で濃度依存性抗腫瘍効果を認めた.VCR (0.06 mg/kg/day×6), PEP (0.9 mg/kg/day×6), MTX(0.6 mg/kg/day×6)では, 一過性の抑制効果を認めた.Ara-C (3 mg/kg/day×6), 5-FU (30 mg/kg/day×6)は全経過を通じて無効であった.2) VPM 3剤群(VCR+Ara-C+5-FU)およびCis CF 3剤群(CDDP+Ara-C+5-FU)投与では, 前者において時間依存性の抑制効果を認め, 後者ではCDDP単剤投与群と同等以上の効果を認めた.BT-11株の系においては, 各種多剤併用療法につき検討したが, VPM-CisCF第2法が有効で, 比較として用いた.WilliamsらのCDDP+ADM+5-FUおよびYagodaのCDDP+CPM+ADMと比べても優るとも劣らないものであった.また, 体重減少で評価した副作用を加味した有用性の点では, 第2法が有意に優れていた.3) VPM-CisCF多剤併用療法において, 第1法および第2法のG2M期同調効果をflow cytometryで検討したが, VPM 3剤群投与では4日目に同調効果を認め, 第2法においてより強い効果を認めた.4) VPM-CisCF多剤併用療法では, 第2法が臨床応用のうえで, より有用と考えられた

We examined the chemotherapies with cis-diamminedichloroplatinum (II) (CDDP) alone and in combination, using the human bladder cancer xenografts (BT-8 and BT-11 strains) in athymic nude mice (BALB/C), to establish the most effective and useful method for urothelial cancer in clinical use. First, to assess the anti-tumor activities of single-drug and our devised VPM or CisCF combination chemotherapies, experiments were done using the BT-8 strain bladder cancer (transitional cell carcinoma and grade III). The schedule and dosage of each chemotherapy were as follows. Vincristine (VCR): 0.06 mg/kg, days 1-6, peplomycin (PEP): 0.9 mg/kg, days 1-6, methotrexate (MTX): 0.6 mg/kg, days 1-6, cytosine arabinoside (Ara-C): 3 mg/kg, days 1-6, 5-fluorouracil (5-FU): 30 mg/kg, days 1-6, adriamycin (ADM): 3 mg/kg, days 1-6, cyclophosphamide (CPM): 10 mg/kg, days 1-10, and CDDP: 2.5 mg/kg, days 1-6. These were for single-drug chemotherapies. The VPM combination consisted of VCR (0.06 mg/kg, days 1 and 4), PEP (0.3 mg/kg, days 1-6) and MTX (0.3 mg/kg, days 2, 3, 5 and 6), and the CisCF combination consisted of CDDP (2.5 mg/kg, days 1 and 4), Ara-C (3 mg/kg, days 1 and 4) and 5-FU (15 mg/kg, days 2, 3, 5 and 6). The control group was given normal saline of 0.1 ml/20 g body weight, intraperitoneally. All anti-cancer drugs were also given intraperitoneally. Secondly, to assess the anti-tumor activities of CDDP alone and various modes of combination chemotherapies with or without CDDP, the following experiments were done using the BT-11 strain bladder cancer (a mixed type of transitional cell carcinoma and squamous cell carcinoma). CDDP: 2.5 mg/kg, days 1-6. VPM X 2: VCR (0.04 mg/kg, days 1, 4, 8 and 11), PEP (0.2 mg/kg, days 1-4) and MTX (0.2 mg/kg, days 2, 3, 5, 6, 9, 10, 12 and 13). CisCF X 2: CDDP (2.5 mg/kg, days 1 and 8), Ara-C (3 mg/kg, days 1, 6, 8 and 13) and 5-FU (30 mg/kg, days 3, 4, 5, 10, 11 and 12). VPM-CisCF (I): VCR (0.04 mg/kg, days 1 and 4), PEP (0.2 mg/kg, days 1-7), MTX (0.2 mg/kg, days 2, 3, 5 and 6), CDDP (2.5 mg/kg, day 8), Ara-C (3 mg/kg, days 8 and 13), and 5-FU (30 mg/kg, days 10-12).(ABSTRACT TRUNCATED AT 400 WORDS)