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ヒト肺小細胞癌細胞株 (SBC-3) を用いてMTT assayにより, 新しいpodophyllotoxin誘導体であるNK611の抗腫瘍効果をetoposideおよびteniposideと比較し, さらにSBC-3のetoposide耐性株 (SBC-3/ETP) を用いて交叉耐性に関する検討を行った. 各薬剤の臨床試験におけるarea under the curve (AUC) とMTT assayから得られた50%抑制濃度 (IC50) との比を抗腫瘍効果の強さを示す尺度とみなすと, AUC/IC50比はNK611 13.6, etoposide 13.5, teniposide 90.1であり, NK611の抗腫瘍効果はetoposideと同等であると推定された. 一方, 交叉耐性度 (SBC-3/ETPのIC50/SBC-3のIC50) は, NK611 2.64, etoposide 17.4, teniposide 7.64であり, 交叉耐性はNK611が最も低く, NK611は. etoposideに耐性の肺小細胞癌症例に効果を有する可能性が示唆された.

A new human lymphoma cell line derived from pulmonary non-Hodgkin's lymphoma that developed in a renal transplant recipient was established from the patient's pleural effusion and designated PTLC-1. PTLC-1 grew aggressively in suspension, forming very loose clumps with a doubling time of about 18.9 h. The morphological, chromosomal, and immunophenotypic characteristics of the patient's tumor cells and PTLC-1 cells were very similar. PTLC-1 showed a monoclonal rearrangement of IgH gene and was highly tumorigenic in athymic nude mice. In situ hybridization, Southern blot hybridization and polymerase chain reaction demonstrated the presence of Epstein-Barr virus (EBV) genome in the patient's tumor and PTLC-1. PTLC-1 has been maintained in culture for over 60 months. Since EBV has been implicated in the pathogenesis of post-transplant lymphoma, this new cell line should serve as a useful experimental model for studying the etiology and biology of lymphoma developing in organ transplant recipients.

Background Small cell lung cancer (SCLC) is highly sensitive to chemotherapy. Despite the introduction of intensive combination chemotherapy, long-term disease-free survivors are still rare. The emergence of drug-resistant tumor cells during chemotherapy is presumed to be the major cause of poor outcome. Methods A pilot Phase II study of hybrid chemotherapy for patients with SCLC was conducted between October 1986 and March 1988. Dose and schedule for each drug in the regimen were as follows: cyclophosphamide, 700 mg/m2 intravenously (IV), day 1; doxorubicin, 30 mg/m2 IV, day 1; vincristine, 1.4 mg/m2 IV, day 1; cisplatin, 60 mg/m2 IV, day 8; and etoposide, 100 mg/m2 IV, days 8 and 9. Courses were repeated every 4 weeks for up to six cycles. Patients with limited disease (LD) received chest irradiation of 5000 cGy when a maximal response was achieved. Only patients with LD who achieved a complete response (CR) received prophylactic cranial irradiation of 3000 cGy. Results Thirty-six patients were enrolled and fully evaluated for tumor response and toxicity. All 20 patients with LD responded to the regimen, and 14 (70%) of those achieved a CR. Of 16 patients with extensive disease (ED), 7 CR and 7 partial responses were noted, indicating an overall response rate of 88%. The median survival time was 23.6 months for patients with LD and 12.6 months for those with ED. Myelosuppression was the major toxicity, but it was generally well tolerated. Conclusions These results indicate that the hybrid regimen is a highly active one for the treatment of patients with SCLC and warrants additional clinical trials.

A case of common variable immunodeficiency (CVID) who developed non-Hodgkin's lymphoma (NHL) of the rectum is reported. A 22-year-old male student in whom CVID was diagnosed at 7 years of age was referred to our department for the treatment of rectal NHL. The patient had stage IE disease confined to the rectum after clinical diagnostic procedures. He was initially treated with radiation therapy alone, but a relapse soon occurred in theparaaortic lymph nodes. He was successfully treated with CHOP-Bleo chemotherapy and supplementation with immunoglobulin preparations. He has since remained free of NHL and infectious complications for over 30 months despite his persistent immunodeficiency.(Internal Medicine 32: 152-155, 1993)

Between April 1981 and December 1987, 148 patients with newly diagnosed small cell lung cancer (SCLC) were treated using combination chemotherapy with or without thoracic irradiation and prophylactic cranial irradiation (PCI) in a series of cooperative therapeutic trials. With a minimum follow-up of 4.7 years, 13 (9%) patients survived and were free of SCLC. These included 11 (15%) of 76 patients with limited disease and two (3%) of 72 patients with extensive disease. Three died without any evidence of SCLC (one each from second leukemia, non-small cell lung cancer, and unrelated disease). The remaining 10 (7%) patients are currently alive and free of SCLC beyond 4.7 years. Since late relapse beyond 5 years is a very rare event, these patients may have been cured. However, late toxicity of PCI must be kept in mind. Three among the 10 patients have suffered from neuropsychologic symptoms of varying degrees in severity. Although the long-term survival rate is a benchmark in the treatment of SCLC, modifications of therapy that may potentially avoid such toxicities should be considered hereafter.

多剤併用療法のプロトコールスタディーにエントリーした切除不能の肺非小細胞癌164例を対象に, 治療前の29のパラメーターについて予後因子の解析を行った. x2検定, generalized Wilcoxon検定による単因子解析では, 肝転移の有無が予後に最も強い影響を及ぼし, 次いで血清アルブミン, 転移臓器の数, CRP, 血清NSE, 病期, 骨転移の有無, コリンエステラーゼ, ヘモグロビン, performance status (PS), 化学療法の種類, 骨髄転移の有無の順に有意性が示された. Coxの比例ハザードモデルを用いた多変量解析では, 生存期間に最も大きく寄与するのは血清アルブミンであり, 次いで化学療法の種類, 病期, PS, LDHが生存期間に対して有意の寄与を示すことが確認された. 単因子解析, 多変量解析のいずれにおいても化学療法の種類が生存期間に対して有意の影響を及ぼすことが示されており, 進展期肺非小細胞癌の治療における化学療法の有用性を示唆する所見と考えられる.

taxol (西洋イチイの樹皮から抽出された植物アルカロイド) のヒト肺小細胞癌細胞株 (SBC-2, 3, 4, 7), 腺癌株 (ABC-1), 扁平上皮癌株 (EBC-1) に対する抗腫瘍効果をMTT assayを用いて検討し, さらにSBC-3のadriamycin, etoposide, およびcisplatin耐性株 (SBC-3/ADM100, SBC-3/ETP, SBC-3/CDDP) を用いて交叉耐性に関する検討を行った. 50%抑制濃度を基準に評価した場合, taxo1は検討した全ての細胞株においてadriamycin, etoposide, cisplatinよりもすぐれた抗腫瘍効果を示した. またtaxolはSBC-3/ADM100, SBC-3/ETPに対して, それぞれ1420倍, 109倍と高い交叉耐性を示したが, SBC-3/CDDPには交叉耐性を示さなかった.すなわちtaxolは現在肺癌化学療法の主体となっているadriamycin, etoposide, cisplatinよりも肺癌に対する抗腫瘍活性が高く, しかもcisplatinとの交叉耐性は乏しいと考えられた

症例: 28歳女性.主訴:胸部異常陰影.会社検診にて胸部異常陰影を指摘され,第1回目入院となった.この時胸部陰影の他に汎血球減少が認められた.肺結核の疑いにて5ヵ月間抗結核療法を行うも陰影は改善しないため,気管支肺胞洗浄(BAL)および経気管支的肺生検(TBLB)が施行された. BALではリンパ球増多, CD 3, CD 8陽性細胞の増加とCD 4/CD 8比の低下が認められた.また肺胞マクロファージ機能のうち遊走能の亢進と水解酵素活性の低下が認められた. TBLBでは器質化肺炎の像を呈していた.そこでステロイドによる治療を行ったところ,胸部陰影は改善した.その後外来にて経過観察を行っていたが,発熱するようになり第2回目入院となった.この時肝脾腫があり,検査では貧血,白血球減少, LDHの高値,凝固検査の異常を認めた.入院後皮膚に発赤を伴う結節が出現し,同部を生検したところ,非化膿性小葉性脂肪織炎を認めた.組織像,臨床症状よりcytophagic histiocytic panniculitis (CHP)と診断した.ステロイドを増量するも症状改善しないため, ciclosporin Aを投与したところ,症状,検査所見の劇的な改善がみられた. BALにてリンパ球増多が認められ, ciclosporin Aが奏功したことより,本疾患ではマクロファージのみならずリンパ球の異常も示唆された.

1983年より当科に入院した肺癌340例のうち4例 (1.2%) に手指への転移を認めた.組織型は小細胞癌2例, 腺癌1例, 扁平上皮癌1例であり, 1例が指骨のみへの転移, 1例が骨および皮膚・軟部組織への転移, 2例が皮膚・軟部組織のみへの転移であった.症状は同部の腫脹と疹痛を全例に認めた.手指への転移は, 全身病変悪化の部分症状として発現し, 全例転移発現後6カ月以内に死亡した.悪性腫瘍の手指への転移は非常にまれであり, また予後不良を示唆する徴候と思われる.

We describe the spontaneous regression of a malignant pleural mesothelioma with left pleural effusion, chest pain, and a high fever (38° to 39°C) in a 37-year-old man. The patient was referred to us because multiple nodules were seen on his chest radiograph after he was successfully treated with thoracocentesis and conventional antibiotic therapy for pleural effusion. Our diagnosis was malignant pleural mesothelioma, based on histologic findings in a biopsy specimen obtained during thoracoscopy. Interestingly, the tumors markedly regressed without treatment, and the patient was doing well more than 5 months after the cancer was diagnosed. The spontaneous regression of malignant pleural mesothelioma is rare, and this may represent the first case report.

Irinotecan is one of the most active drugs used in the treatment of small cell lung cancer (SCLC). 7-Ethyl-10-hydroxy-camptothecin (SN-38) is an active metabolite of irinotecan. We established an SN-38-resistant subline (SBC-3/SN-38) by continuous exposure of SN-38 to a human SCLC cell line, SBC-3. Using the 3-[4, 5-dimethyl-thiazol-2-yl] 2, 5-diphenyltetrazolium bromide assay, we evaluated the cytotoxicity of 17 anticancer agents. The SBC-3/SN-38 cells were 73-fold more resistant than the parental SBC-3 cells to SN-38 and showed cross-resistance not only to topoisomerase (topo) I inhibitors (irinotecan and topotecan), but also to topo II inhibitors (adriamycin and etoposide), antimicrotubule agents (vincristine, vindesine, vinorelbine and docetaxel), alkylating agents (cyclophosphamide and ifosfamide), platinum (cisplatin and carboplatin) and antifolate (methotrexate). Interestingly, the resistant subline reserved the sensitivity to bleomycin and 5-fluorouracil. The SBC-3/SN-38 cells had decreased topo I and II activity compared to the parent cells. The SN-38-resistant cell line, SBC-3/SN-38, will be useful to elucidate the mechanism of action of the topo I inhibitors.

We investigated the changes in cellular components and neutrophil chemotactic factors in pleural fluid from 19 lung cancer patients who received intrapleural injection of OK-432 to treat malignant pleurisy. Not only neutrophil chemotactic activity (NCA) but also neutrophil count and percentage were increased significantly at 6 hours after OK-432 injection. The neutrophil count was significantly correlated with NCA level. The levels of C5a and IL-8 in pleural fluid were increased significantly after OK-432 injection. The increased IL-8 level was associated with a increase of both NCA and neutrophil count. OK-432 treatment also induced a marked increase of IL-1β and IL-6 in pleural fluid. Thus, intrapleural injection of OK-432 induced production of neutrophil chemotactic factors (IL-8 and C5a) and cytokines (IL-1β and IL-6), which eventually attracted neutrophils into the pleural space. These observations suggest that neutrophil migration mediated by these factors and cytokines may contribute to the sclerosing effects of OK-432 treatment.(Internal Medicine 34: 352-356, 1995)

Brochoalveolar lavage (BAL) were performed in 28 patients with sarcoidosis and in 31 normal subjects. In control subjects, the numbers of mononuclear cells and macrophages in smokers were significantly increased in comparison to nonsmokers (p

肺小細胞癌の完全寛解中に急性骨髄性白血病 (AML) を発症した興味ある1症例を経験した.症例は, 肺小細胞癌の確定診断のもとに, 多剤併用交替療法と胸部放射線療法により完全寛解となった.治療開始後22ヵ月頃より血小板減少が出現し, 骨髄塗抹標本で, アウエル小体を伴う骨髄芽球が少数認められ, さらに7ヵ月後, AMLに移行し死亡した.病理解剖の結果, 肺小細胞癌の残存は全く認められず, 肺小細胞癌は完全寛解の状態であった.

1968年以降10年間にわれわれの施設で取扱かった小細胞癌症例について, 化学療法の成績を中心に検討を加えた. その結果, 多剤併用療法は単独療法に比べ有効率が高く, 多剤併用療法の中では, cyclophosphamide, vincristine, methotrexate, procarbazine 4剤併用療法の効果がもっとも優れていた. 治療効果別の生存期間をみると, 腫瘤完全退縮例のmedian survivalは12ヶ月以上 (平均18.4ヶ月以上), 部分退縮例では8.4ケ月 (7.8ヶ月), 無効例では4.3ヶ月 (4.2ヶ月) であり, 有効例と無効例の生存期間には明らかな差が示された.

肺小細胞癌69例の治療経過中に2例の癌性髄膜症を経験した.症例1は, 化学療法により完全寛解を得た後, 癌性髄膜症で再発し, 発症後7週間で死亡した.剖検時, 腫瘍細胞は髄膜のみに認められ, 癌性髄膜症の発症がなければさらに長期の生存が可能と思われた.症例2は, 化学療法による部分寛解中に癌性髄膜症を発症し, 脳脊髄への放射線照射と抗癌剤髄腔内投与が著効を示し, 発症後9ヶ月間の長期にわたり癌性髄膜症を管理し得た.

Two cases of so-called Lennert's lymphoma, which is characterized by massive infiltraions of focally aggregated epithelioid cells, are presented. Since this lesion was particularly emphasized by Lennert and Mestdagh in 1968, the major conflicting issue has been focussed on its precise disease entity whether this is an independent or already-established lymphoproliferative disorder. Based on our experiences, we are rather inclined to regard this lesion to be “a curious histologic variant of an already-established disease entity”. In order to investigate its precise disease entity and also in view of a possible significance of the presence of epithelioid histiocytes in the lymph nodes and of tonsillar involvement in relation to imunocompetence of the patients, further accumulation of similar cases is required.

Streptococcal agent OK-432 was administered at maintenance levels with conventional inductive chemotherapeutic agents to stage III and IV lung cancer patients. Survival rates were longer in patients treated with OK-432 than in patients treated without OK-432. An enhancement of lymphocyte blastogenic activity and a delayed PPD skin reaction were found in patients treated by OK-432. A low grade fever was present as a side effect of this agent in some patients. The results suggest that OTK-432 may be useful immunotherapeutic agent in combination with induction chemotherapy in reducing host damage in advanced stages of lung cancer.

In vivo animal studies support the concept that monocytes and macrophages are important in the immune surveillance of oncogenesis and that in vitro activated murine macrophages are cytocidal for tumour cells. In this study, the tumour cell cytotoxic activity of human peripheral blood monocytes was examined by measuring the inhibition of 3H-thymidine uptake in the human cancer cell line, established in our laboratory from human squamous cell lung cancer. The monocytes from 8 of the 31 lung cancer patients (26%) showed a percentage growth inhibition of less than 69.8%, which exceeded the 95% confidence limits of the percentage growth inhibition observed with healthy control monocytes. On the other hand, among the 16 sarcoidosis and the 8 tuberculosis cases no value was below 69.8%. However, there was no significant difference between the growth inhibition and the clinical stages or histological type. When OK-432, a Streptococcal agent, was administered in vivo to patients with lung cancer, an elevation of the growth inhibition was observed in 7 out of 8 patients. It was confirmed that the tumour cell cytostatic activity of the monocyte is suppressed in patients with lung cancer, and these monocyte deficits hinder the inhibition of tumour growth and metastasis.

The in vivo antitumor activity of NCS-immune immunoglobulin G (IgG) [Neocarzinostatin (NCS) conjugated with rabbit IgG antibody against a human leukemia cell line (NALL-1)] was evaluated in immunosuppressed newborn Syrian hamsters into which a transplantable human leukemia cell line, BALL-1 was implanted. After intraperitoneal (i.p.) injection of the conjugate, hamsters preinoculated i.p. with BALL-1 cells survived longer than hamsters treated with control solutions (p less than 0.01). The control solutions were NCS, immune IgG, a mixture of NCS and immune IgG, NCS-normal IgG conjugate and physiological saline. There was no change in body weight in the NCS-immune IgG-treated hamsters. The growth of subcutaneously (s.c.) implanted BALL-1 tumors was also inhibited by i.p. administration of NCS-immune IgG; however, the degree of inhibition was not significantly different from that obtained by administration of NCS alone, a mixture of NCS and immune IgG or NCS-normal IgG conjugate. These results indicate that NCS-immune IgG was effective against i.p. BALL-1 tumors, but was less effective against s.c. implanted tumors.

In order to assess the effectiveness of chest irradiation in addition to intensive chemotherapy in limited stage small cell lung cancer, 50 patients were randomized to receive either chemotherapy alone or chemotherapy plus chest irradiation, between April 1981 and October 1985. The chemotherapy regimen consisted of a four-drug combination of cyclophosphamide, vincristine, methotrexate, and procarbazine, and a three-drug combination of etoposide, adriamycin, and nimustine, given alternately every 8 weeks. One group of 26 patients received the chemotherapy alone, and another group of 24 patients received chest irradiation with 40 Gy between cycles 1 and 2 of the chemotherapy. Complete response rates were quite similar in the two groups; 50% for those receiving chemotherapy alone, and 59% for those receiving chemotherapy plus chest irradiation. There were no significant differences in median survival (15 months versus 12 months) and in long-term survival rates between the two groups with a median follow-up period of 26 months. The combined modality treatment was more toxic than chemotherapy alone; two patients receiving such treatment died of radiation pneumonitis. It is concluded that chest irradiation combined with chemotherapy does not affect the response rate, survival, or pattern of recurrence in patients with limited stage small cell lung cancer.

The effects of temperature on the anthracycline antibiotics-induced cell kill of DND-1A human malignant melanoma (MM) and DND-39A Burkitt's lymphoma (BL) cell lines were studied by means of a clonogenic assay. The two cell lines differed in sensitivity when exposed to heat: The MM cells were unaffected by hyperthermia (42 degrees C), whereas BL cells were sensitive to this temperature. With the MM cells, hyperthermia potentiated the cytotoxic effects of doxorubicin (ADM), daunorubicin, mitoxantrone (DHAD), and quelamycin but did not enhance that of aclacinomycin (ACM). Conversely, the exposure of cells to the anthracycline compounds at 0 degree C resulted in almost complete disappearance of cell kill effects except with ACM; ACM retained substantial cell kill effects even at the given low temperature. For BL cells, ADM- or DHAD-induced cell lethality was also potentiated by hyperthermia; ACM produced only additive cell kill. At 0 degree C, ACM's effects virtually disappeared. These data indicate that human tumor cell lines have a substantial variety in heat sensitivity and that not every anthracycline antitumor agent is potentiated by temperature. ACM's thermoresponse is unique among anthracycline antibiotics studied. Additionally, it was shown that normothermic cell kill by ADM was not affected by hyperthermic preheating; however, preheating of appropriate duration produced important influence on subsequent hyperthermic ADM-induced cell kill.

Rabbit xenoantiserum was produced against a human leukemia cell line (NALL-1) derived from a patient with acute lymphoblastic leukemia, and IgG was purified. Anti-NALL-1 rabbit IgG was reacted with NCS, an unique membrane-reactive anticancer antibiotic, in the presence of water-soluble carbodiimide. The resulting mixture was concentrated and chromatographed on a Sephadex G-200 column. The first and second fractions were shown by immunoelectrophoresis and the Ouchterlony double-diffusion method to contain NCS-IgG but not free NCS. The conjugates inhibited the growth of Sarcina lutea, and the growth and 3H-TdR incorporation of NALL-1 cells. A membrane immunofluorescent test with FITC-labeled rabbit anti-NCS and goat anti-rabbit IgG antibodies demonstrated specific localization of NCS-IgG on NALL-1 cell surfaces. These results indicate that IgG-bound NCS retained both NCS and antibody activities, and thus should be useful for cancer therapy.