Cisplatin-resistant human small cell lung cancer cell line shows collateral sensitivity to vinca alkaloids.

A cisplatin-resistant cell line, SBC-3/CDDP, was established from a human small-cell lung cancer cell line, SBC-3. The SBC-3/CDDP cells were 13.1-fold more resistant to cisplatin than the parent SBC-3 cells. We investigated the cellular changes of this cell line with regard to the development of resistance to cisplatin. The SBC-3/CDDP cells showed various characteristics as follows: a) increased intracellular glutathione and glutathione S-transferase content b) decreased intracellular accumulation of cisplatin, c) increased topoisomerase I activity and the same topoisomerase II activity as the parent SBC-3 cells, and 4) strong cross-resistance to the platinum analogues and mitomycin C, moderate cross-resistance to 7-ethyl-10-hydroxy-camptothecin (SN-38), 4-hydroperoxy cyclophosphamide, etoposide, Adriamycin and methotrexate, and collateral sensitivity to vinca alkaloids and 5-fluorouracil. From these observations, the SBC-3/CDDP cells could be useful as a well characterized cisplatin-resistant cell line, and the resistance pattem in this cell line will give us much information for eradication of cisplatin-resistant tumor cells.

Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan.

BACKGROUND: Hepatitis B after the withdrawal of cytotoxic chemotherapy in hepatitis B virus (HBV) carriers is well known and may lead to fatal hepatic failure. We retrospectively analyzed the prevalence of HBV carriers, the incidence, and the risk factors of hepatitis B in the treatment of malignant lymphoma. PATIENTS AND METHODS: HBV carriers were defined as patients with positive HBs-antigen, either with normal or abnormal serum aminotransferase level at patient presentation. Questionnaires to the members of the Japan Lymphoma Treatment Study Group included general information, details about HBV carriers, and further information about hepatitis B. RESULTS: Among 1380 patients collected from eight institutions, 45 patients (3.26%) were determined to be HBV carriers, Hepatitis B developed in 17 of the HBV carrying patients (37.8%). Seven of those 17 (41.2%) died of hepatic failure. Hepatitis developed at a high rate in patients who were negative for HBe-antigen (50%), and who had received second- or third-generation chemotherapy (63.2%). CONCLUSION: We confirmed that hepatitis B developed with high frequency in HBV carriers with malignant lymphoma. Moreover, hepatitis often resulted in fatal hepatic failure. It is necessary to prevent the hepatitis B developing in HBV carriers when receiving intensive chemotherapy for malignant lymphoma.

[Chemotherapy for small-cell lung cancer].

Here we review the current treatments for small-cell lung cancer. Cisplatin and etoposide, combined with concurrent or alternating thoracic irradiation, have been considered to be the standard therapy for patients with limited disease. Dose-intensive weekly chemotherapy and high-dose chemotherapy with autologous stem cell transplantation have failed to increase survival in patients with extensive disease. Promising new drugs such as irinotecan and taxol may improve survival in patients with extensive disease.

[Clinical evaluation of 201TI single photon emission computed tomography in patients with large opacities due to silicosis with bronchogenic carcinoma].

201T1 single photon emission computed tomography (201T1 SPECT) was used to evaluate 18 patients with large opacities due to silicosis and 22 others with bronchogenic carcinoma. An early scan and a delayed scan were obtained and the retention index was calculated from the early ratio and the delayed ratio. In patients with silicosis, the retention index and the two ratios were significantly lower than in the patients with bronchogenic carcinoma (p < 0.01). In patients with stable shadows on chest X-ray films due to large opacities of silicosis, the delayed ratio was the same as or lower than the early ratio. However, in patients with silicosis who had high activity in large opacities, the delayed ratio was higher than the early ratio. These results suggest that 201)T1 SPECT is useful for evaluating the activity of large opacities in patients with silicosis and for differentiating large opacities caused by silicosis from those caused by bronchogenic carcinoma.

[Recurrence of the acute respiratory distress syndrome in a patient with liver cirrhosis and diabetes mellitus].

The acute respiratory distress syndrome developed twice within 4 months in a patient with liver cirrhosis and diabetes mellitus. The diagnosis was made from the diffuse alveolar shadows seen on a chest X-ray film and a lung injury score of 3.3. The initial episode resolved quickly with steroid pulse therapy. The second episode resolved to some extent after the same therapy, but the patient died of hepatic and renal failure followed by acute pneumonia. The causes of the first and second episodes were considered to be different and the outcome depended on liver and kidney function. We report this case because the acute respiratory distress syndrome rarely occurs within 4 months.

[Moderately differentiated adenocarcinoma of the lung presenting as multiple intrapulmonary metastases with thin-walled cavities].

A 63-year-old woman complaining of a non-productive cough was referred to our hospital. A chest X-ray film and computed tomographic scan showed a large mass in the S9 region of the right lung, and many intrapulmonary nodules with thin-walled cavities. A transbronchial biopsy specimen revealed moderately differentiated adenocarcinoma of bronchial gland origin. By the end of four cycles of chemotherapy with vindesine, ifosfamide, and cisplatin, the primary mass had markedly regressed, the many metastases had disappeared, and a few bullous lesions remained. On the second admission, many intrapulmonary metastases and cavities were seen again. Although some of the cavities may have been associated with regrowth of residual cancer cells around the remaining bullae, some nodules showed newly-developed thin-walled cavities, and in others bullous lesions developed again. These observations indicate that a check valve mechanism may operate in the formation of the thin-walled cavities.

[Gingival metastasis of large-cell lung cancer that produced G-CSF].

A 68-year-old man was referred to our hospital for further examination of a gingival mass. Chest radiographs and magnetic resonance imaging disclosed a bulky mass originating in the upper portion of the left lung, in contact with a chronic empyema lesion that first occurred after resection for pulmonary tuberculosis. Examination of a specimen obtained by percutaneous needle biopsy of the mass led to the diagnosis of large-cell carcinoma. Laboratory findings on admission showed marked leukocytosis (48,100/microliter) without evidence of severe a bacterial infection. The level of G-CSF in serum was abnormally high (246 pg/ml, normal value: < 30 pg/ml). Chemotherapy with vindesine, ifosfamide, and cisplatin resulted in shrinkage of the gingival mass, and a decrease in the G-CSF level to 66 pg/ml. Immunohistochemical staining with an anti-G-CSF monoclonal antibody to the primary lung tumor and the gingival mass obtained at autopsy was positive for cytoplasmic G-CSF.

[Induction chemotherapy followed by adjuvant surgery (IC-AS) in patients with stage I-II small cell lung cancer (SCLC)].

Ten patients with stage I-II SCLC received IC-AS between 1984 and 1993. As induction chemotherapy, COMP-VAN alternating chemotherapy and CAV-PVP hybrid chemotherapy were administered. The former consisted of a 4-drug combination of cyclophosphamide (CPA), vincristine (VCR), methotrexate (MTX) and procarbazine alternated with a 3-drug combination of etoposide (ETP), adriamycin (ADM) and nimustine every 4 weeks. In the latter, a 3-drug combination of CPA, ADM and VCR given on day 1, and a 2-drug combination of ETP and cisplatin on day 8, were repeated every 4 weeks. All the patients had an objective response, including one complete response by induction chemotherapy. Post-operative pathology revealed SCLC in 4 patients, adenocarcinoma in 2 and no tumor (pathological CR) in 4. Four patients relapsed, and a intrathoracic relapse was experienced in only 2 patients. Six patients have died: 3 from relapsing SCLC, 2 from stomach cancer, and 1 from squamous lung cancer, who was salvaged from relapsing SCLC. The median survival time was 27.5 months, and the 3-year survival rate 37.5%. These results indicate that IC-AS is highly effective for stage I-II SCLC and warrant additional studies comparing IC-AS with chemo-radiotherapy.

OK-432 induces production of neutrophil chemotactic factors in malignant pleural effusion.

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-1 beta 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-1 beta 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.

Epstein-Barr virus-associated post-transplant non-Hodgkin's lymphoma: establishment and characterization of a new cell line.

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.

[Treatment of small cell lung cancer].

This paper overviews the recent treatment results for small cell lung cancer. The last decade has brought only a small improvement, supposedly, mainly due to the development of drug resistance. However, current trials of non-cross-resistant chemotherapy, dose-intensive weekly chemotherapy, late intensification with autologous bone marrow transplantation, and combined modality treatment with thoracic irradiation have shown a substantial advance in the treatment of small cell lung cancer.

[Occurrence of follicular small cleaved cell lymphoma following chemotherapy for diffuse large cell lymphoma].

A 59-year-old man was admitted in July, 1985 because of generalized lymphadenopathy and hypercalcemia. The biopsy specimen of the left inguinal lymph node showed diffuse large cell lymphoma. He achieved a complete remission (CR) in July, 1986 by CHOP therapy. In January, 1992, he visited the outpatient clinic with splenomegaly, and swelling of the left axillary and left supraclavicular lymph nodes. The biopsy specimen of the axillary lymph node showed follicular small cleaved cell lymphoma. Because the spleen and the lymph nodes regressed after the biopsy, he has been followed up without any specific treatment for lymphoma. Histologic change from low-grade lymphoma into more aggressive histologic pattern is well documented. However the converse phenomenon, occurrence of low-grade lymphoma after intermediate-, or high-grade lymphoma has rarely been reported. Histological examination is mandatory when a patient with diffuse large cell lymphoma is suspected to have relapsing disease after the long-term CR.

[Successful treatment of two patients with advanced gastric cancer by neoadjuvant chemotherapy with EAP regimen].

Two patients with unresectable gastric cancer accompanied with multiple liver metastases were treated with a 3-drug combination consisting of etoposide, adriamycin, and cisplatin (EAP) as neoadjuvant chemotherapy. After confirmation of maximal response to EAP, both patients received surgical resection of the primary tumor and infusion of cisplatin and 5-FU into hepatic artery, and they survived 15.0 and 15.8 months, respectively. These results indicate that neoadjuvant chemotherapy with EAP regimen is useful in the treatment of advanced gastric cancer.

Inhibitory effects of cholera toxin on in vitro growth of human lung cancer cell lines.

Cholera toxin (CT) inhibited the growth of three out of 10 small cell lung cancer (SCLC) cell lines and two out of seven non-small cell lung cancer (NSCLC) cell lines when tested by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. These CT-sensitive as well as CT-resistant cell lines bound well to the non-toxic CT-B subunit-fluorescein isothiocyanate conjugate (FITC-CTB) when assayed by flow cytometry. Using the reaction of horseradish peroxidase-conjugated CT-B (HRP-CTB) on thin-layer chromatography (TLC), we analyzed gangliosides extracted from SCLC cell lines, CT-resistant SBC-1, minimally CT-sensitive SBC-3 and CT-sensitive SBC-5. HRP-CTB was found to react not only with GM1, but also with Fuc-GM1, GD1b and other gangliosides on TLC. Although CT-resistant SBC-1 cells bound well to FITC-CTB, the binding of gangliosides extracted from SBC-1 cells to HRP-CTB was markedly decreased when compared to those from CT-sensitive SBC-5 cells. The CT resistance of the minimally CT-sensitive SBC-3 cell lines, which binds weakly FITC-CTB and HRP-CTB, was partially reversed by exogenous GM1 pretreatment. These observations suggest that the amount of gangliosides, such as GM1, Fuc-GM1 and GD1b, on the cells, rather than the CT-binding ability to the cells, plays a major role in cytotoxicity by CT.

[CAV-PVP chemotherapy and sequential thoracic irradiation (TI) for patients with limited (LD) small cell lung cancer (SCLC)].

In order to assess the effectiveness of sequential TI for the treatment of LD SCLC, we analyzed 69 patients who had received CAV-PVP chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, cisplatin and etoposide, plus sequential TI between 1986 and 1992. TI was delivered at a total dose of 50 Gy, 5 fractions/week for 5 weeks, once patients achieved a maximal response to chemotherapy. Responding patients also received PCI at a total dose of 30 Gy, 5 fractions/week for 3 weeks. Thirty patients achieved CR by chemotherapy and an additional 10 achieved CR after TI, resulting in a CR rate of 58.0%. Of 40 patients achieving CR, 24 have relapsed so far; the primary (in 15) and the brain (in 4) were the major sites of relapse despite TI and PCI. The median survival time was 18.4 months, with a 2-year survival rate of 39% and 3-year survival rate of 20%. Almost all the patients encountered grade 3 or grade 4 leukopenia while receiving chemotherapy, but the toxicity of TI was generally mild. This treatment is useful for patients with LD SCLC.

Pilot study of cyclophosphamide-doxorubicin-vincristine-cisplatin-etoposide hybrid chemotherapy in small cell lung cancer.

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.

Antitumor activity of platinum analogs against human lung cancer cell lines and tumor specimens.

Antitumor activities of five platinum analogs, including cisplatin, carboplatin, 254-S, DWA2114R, and NK121, were compared using five human lung cancer cell lines and 19 tumor specimens obtained from lung cancer patients. The antitumor activity was evaluated by determining the ratio of the maximum tolerated dose of each drug to the 70% tumor growth inhibitory concentration in a colony assay. Cisplatin was the most potent agent, followed by 254-S and carboplatin. DWA2114R and NK121 were less potent than cisplatin and 254-S. Cross-resistance to adriamycin was also investigated using an adriamycin-resistant small cell lung cancer subline, SBC -3/ADM30. SBC-3/ADM30 was 1.7- to 4.0-fold more resistant to cisplatin, carboplatin, NK121, and DWA2114R, than was the parent line, SBC-3, and the subline was 2.0-fold more sensitive to 254-S. Using SBC-3, in vitro combination effects of etoposide and cisplatin, carboplatin, or 254-S were evaluated by the median-effect principle. Synergism was noted when cisplatin and etoposide were combined at a fixed molar ratio of 1:1. Combination of carboplatin and etoposide showed an additive effect. The combination of 254-S and etoposide was antagonistic at low concentrations, but was markedly synergistic at higher concentrations. These data suggested the efficacy of 254-S in the treatment of lung cancer.

MDR1 gene expression and treatment outcome in small cell lung cancer: MDR1 gene expression as an independent prognostic factor.

We report a preliminary study to determine whether MDR1 gene expression level in small cell lung cancer (SCLC) tumors is a useful predictor of tumor response to chemotherapy and patient survival in association with myc amplification in the tumor. We analyzed 18 patients with SCLC receiving adriamycin and etoposide combination chemotherapy between August 1989 and November 1991; 16 males and 2 females, median age of 68 years, and 7 with limited disease and 11 with extensive disease. MDR1 mRNA expression level and myc family gene amplification were simultaneously determined by polymerase chain reaction using transbronchial biopsy specimens which were obtained at diagnosis. Patients with tumors expressing low MDR1 mRNA responded more favorably to chemotherapy than those with tumors expressing high MDRI mRNA, however, the difference in tumor response was statistically not significant (84.6% versus 40%). The overall survival was significantly shorter in the latter than in the former (7.2 months versus 11.7 months; p = 0.023). The survival of the 4 patients with tumor showing myc family gene amplification was almost identical to that of patients with tumors showing no amplification of the gene (8.2 months versus 8.8 months; p = 0.73). Multivariate Cox's regression analysis supports the notion that MDR1 may be a useful independent prognostic factor.