Makio Wada

LEVELS OF GLUTATHIONES TRANSFERASE π mRNA IN HUMAN LUNG CANCER CELL LINES CORRELATE WITH THE RESISTANCE TO CISPLATIN AND CARBOPLATIN

The amounts of mRNA for glutathione S transferase π (GST π) were significantly lower in 3 human small cell lung cancer (SCLC) cell lines than in 3 non small cell lung cancer (NSCLC) cell lines. The sensitivities of the 3 SCLC cell lines to cisplatin and carboplatin were much higher than those of the 3 NSCLC cell lines. These results indicate that low levels of GST π mRNA expression in SCLC cell lines inversely correlate to high sensitivity to cisplatin and carboplatin, and further suggest that GST π may play an important role in intracellular inactivation of these drugs.

Mutations of the p53 tumour suppressor gene in haematologic neoplasms

Mutations of the p53 tumour suppressor gene have frequently been observed in several types of solid tumours and are believed to be implicated in the development of these tumours. To determine the relevance of p53 mutations in haematologic neoplasms, we performed polymerase chain reaction‐single strand conformation polymorphism analysis on the p53 gene in 45 patients with various types of haematologic neoplasms. In exons 5–8 containing highly conserved regions, mobility shifts indicating sequence alterations were detected in four of the 45 patients, and subsequent sequencing was performed. A point mutation resulting in a novel stop codon was detected at codon 213 in one of 23 cases of chronic myelogenous leukaemia (one of five cases of blast crisis). Point mutations causing amino acid substitutions were detected in one of four cases of myelodysplastic syndrome at codon 195, one of three cases of adult T‐cell leukaemia at codon 281, and one of eight cases of acute lymphoblastic leukaemia at codon 281, and these missense mutations were accompanied by loss of the wild type allele. Patients harbouring these nonsense and missense mutations were in advanced disease stages. These findings suggest that mutational inactivation of the p53 gene is infrequent but is involved in the tumorigenesis of several types of haematologic neoplasms at least in some cases.

Induction therapy consisting of alternating cycles of ranimustine, vincristine, melphalan, dexamethasone and interferon alpha (ROAD-IN) and a randomized comparison of interferon alpha maintenance in multiple myeloma: a co-operative study in Japan.

This pilot study evaluated the efficacy of a new combination chemotherapy with a newly developed nitrosourea derivative ranimustine and evaluated the efficacy of interferon α (IFN‐α) maintenance in previously untreated patients with multiple myeloma (MM). The induction therapy (ROAD‐IN) was a 6‐week regimen consisting of chemotherapy with ranimustine, vincristine (Oncovin), melphalan (Alkeran) and dexamethasone starting on day 1 and IFN‐α, which was administered three times weekly for 3 weeks starting on day 22. This was repeated for three cycles. The responders were subsequently randomized into two groups that received or did not receive IFN‐α as maintenance therapy. Of the 164 patients registered, 161 were evaluated. An objective response to induction therapy was seen in 75% of patients; complete remission (CR) in 38 (24%) and partial remission (PR) in 82 (51%). The median survival for all patients was 3·6 years from registration. The survival of responders (CR + PR) was significantly better than that of non‐responders (median survival 4·3 years vs. 1·4 years; 7‐year survival rate 32% vs. 9%; P < 0·0001). The IFN‐α maintenance did not show any advantage for either response duration or survival. This pilot study demonstrated that a comparatively short period of induction therapy with the ROAD‐IN regimen produced a rather high response rate and a similar survival rate to those achieved with other longer induction regimens, and that good responders to the initial therapy survived significantly longer than non‐responders.

Relation between Nucleolar Size and Growth Characteristics in Small Cell Lung Cancer Cell Lines

Relationships among cytological features, doubling time, S‐phase percentage, expression of myc‐family oncogenes, DNA ploidy and biochemical properties were studied in thirteen small cell lung cancer cell lines. Six cell lines that grew slowly (average doubling time 99 h) and had lower S‐phase percentages (average 32%) showed inconspicuous nncleoli (average area of 1.5 μm2), and the remaining seven cell lines that grew quickly (average doubling time 45 h) and had higher S‐phase percentages (average 44%) showed large and prominent nncleoli (average area of 6.1 μm2). DNA index value obtained from flow cytometric DNA histograms showed that all cell lines except for H‐69 cell line displayed aneuploidy. Ribbon‐like cell arrangements were observed in the 7 cell lines that grew quickly, and in 1 cell line that grew slowly. Biochemically, six slow‐growing cell lines and four fast‐growing cell lines showed high levels of aromatic L‐amino acid decarboxylase activity, while in the remaining three fast‐growing cell lines its level was low. A high level of c‐myc or N‐myc oncogene expression was observed in all 7 cell lines that grew quickly, but not in any of the 6 cell lines that grew slowly. It appears that small cell lung cancer cell lines that grow quickly can be expected to have large nucleoli and ribbon‐like cell arrangements and to express high levels of mycfamily oncogenes, and that nucleolar size is a good indicator for growth characteristics.

Pure red cell aplasia (PRCA) with thymoma: a possible distinct clinical entity distinct from large granular lymphocyte (LGL) leukemia.

Letters and correspondence submitted for possible publication mustbe identified as such. Text length must not exceed 500 words andfive bibliographic references. A single concise figure or table may beincluded if it is essential to support the communication. Letters nottyped double-spaced will not be considered for publication. Letters notmeeting these specifications will not be returned to authors. Letters tothe Editor are utilized to communicate a single novel observation orfinding.Correspondence is to be used to supplement or constructivelycomment on the contents of a publication in the journal and cannotexceed the restrictions forLetters to the Editor. The Editor reservesthe right to shorten text, delete objectional comments, and makeother changes to comply with the style of the journal. Permission forpublication must be appended as a postscript. Submissions must besent to Paul Chervenick, M.D., Editor of Brief Reports/Letters toEditors, American Journal of Hematology, H. Lee Moffitt CancerCenter, University of South Florida, 12902 Magnolia Drive, Tampa,FL 33612 to permit rapid consideration for publication.Pure Red Cell Aplasia (PRCA) With Thymoma: A PossibleDistinct Clinical Entity Distinct From Large GranularLymphocyte (LGL) LeukemiaTo the Editor: Semenzato et al. proposed new criteria for large granularlymphocyte (LGL) leukemia because patients with low levels of GL weresimilar to those with levels greater than 2,000 GL/ml [1]. LGL leukemia isa GL proliferative disease often accompanied by pure red cell aplasia(PRCA). T-cell LGL leukemia is a clonal disease, and the phenotype ofleukemic cells is CD3

Selection of Radioresistant Cells by Vitamin A Deficiency in a Small Cell Lung Cancer Cell Line

Radiation sensitivity of a human small cell lung cancer cell line, Lu‐134‐B cells, cultured in serum‐supplemented medium and of cells transferred to and cultured in delipidized serum‐supplemented (vitamin A‐deficient) medium was studied. The cells cultured in serum‐supplemented medium showed the phenotype of classic small cell lung cancer sensitive to radiation, while cells transferred to delipidized serum‐supplemented medium showed partial squamous cell differentiation and became resistant to radiation. These results suggest that some small cell lung cancer cells in vitro change their morphology and radiosensitivity depending on the culture conditions. The change in radiosensitivity was reproducible, and was not reversible by culture of the radioresistant cells in delipidized serum‐supplemented medium with addition of retinoic acid (vitamin A‐sufficient medium) for two months, although squamous cells disappeared. Acquisition of radioresistancy was considered to occur as the result of clonal selective growth in delipidized medium of a minor cell population in the original cell culture, based on a study of chromosome number. It was also found that there was no association of myc‐family oncogenes with the changes of radiosensitivity in this cell line.

A new diagnostic method of liver cancer: using fluorescence peritoneoscopy (III)

Fluorescence peri toneoscopy was used for the invest igation of l iver cancer under vital staining with acridine orange. Acridine orange was adminis tered orally 3 hours or more pr ior to the examinat ion . The s tandard dosage of acridine orange was 10mgm/kgm body weight. By fluorescence peritoneoscopy, a metallic yellow fluorescence was observed in mal ignant tissue, while green fluorescence was observed in normal tissue. The fluorescence observed in pat ients wi th hepati t is , those with l iver c i r rhos is and those wi th l iver cancer was green, yellowish green and metall ic yellow, respectively. In the fluorescence microscopic invest igat ion of the specimen obtained by needle biopsy from various human liver, a metallic yellow fluorescence was observed in both nuclei and cytoplasm of mal ignant l iver cell. The fluorescence color of nuclei was s t ronger than tha t of o ther par t s of the cell. A green ish fa int yellow fluorescence was shown in normal intact cell and a greenish s trong yellow fluorescence was shown in prol i ferat ive connect ive t issue. It is suspected tha t fluorescence peri toneoscopy under vital s ta in ing of the liver cell with acridine orange is a useful method for rapid screening and differential diagnosis wi th other l iver diseases, when used with selective l iver angiography or hepatoscint iphotography or other procedure simultaneously.

The treatment for bile excretion in liver biopsy through peritoneoscopy

Carbohydrate metabol i sms of the isolated perfused l iver f rom normal rat , and ra ts with fatty, fibrotic and c i r rhot ic l iver derived from choline deficiency, were studied. The isolated ra t l iver perfusions were carr ied out dur ing 2 hours with 200 ml of saline diluted, heparinized ra t blood, using Sellers-Okuyamas perfusion apparatus. Glucose, lactic acid, pyruvic acid and urea concentrat ion in perfusate were determined respectively. In the normal l iver perfusion, glucose level in perfusate increased as a resul t of glycogenolysis and gluconeogenesis. Then, lactic acid level decreased according as the s t imula t ion of gluconeogenesis. In the diseased l iver perfusion, in accordance with the development of histologic findings f rom fat ty l iver via fibrosis to cirrhosis , glucose level tended to decrease and lactic acid level tended to increase. Urea format ion in the diseased liver perfusion was lower than in the normal l iver perfusion. These data suggest tha t according as the development of l iver injuries, carbohydrate metabolism, especially gluconeogenesis is suppressed m.arkedly.