Growth and survival of B-chronic lymphocytic leukaemia cells

Although chronic lymphocytic leukaemia of B-cell type (B-CLL) is the most common form of leukaemia in the Western world, several questions about the biology of B-CLL remain to be clarified. To obtain a conceptual model for B-CLL, defined as a relentless accumulation of resting B-CLL cells, it is particularly relevant to ask which cell type is the normal counterpart of B-CLL; what is the site of proliferation; which signals are involved in the recruitment and induction of proliferation and which signals contribute to the survival of the B-CLL cells? The significance of the studies on B-CLL cellsin vitro for the interpretation of thein vivo situation may be questioned since they oversimplify the multiple and complex cellular interactions that occurin vivo. However, thein vitro studies have been instrumental in elucidating signals that may regulate growth, differentiation and survival of B-CLL cells. This knowledge, herein reviewed, can be used to put forward a hypothesis on B-CLL cell regulationin vivo.     

Enhancement of Radiation Response by Paclitaxel in Mice According to Different Treatment Schedules

Purpose: The aim of our study was to determine if paclitaxel could be used as a radiosensitizer in vivo.

Materials and methods: Paclitaxel was tested as a single agent and combined with an X-ray treatment. Paclitaxel was administered i.p. in doses from 30 to 120 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Tumor growth delay (TGD) or tumor control dose (TCD₅₀, radiation dose needed to induce local tumor control in 50% of irradiated animals) and moist desquamation dose (MDD₅₀, radiation dose needed to induce serious moist desquamation in 50% of the non-tumor-bearing feet) were the endpoints. DNA flow cytometric analysis was performed.

Results: DNA analysis demonstrated a G2/M block of tumor cells and a depletion of cells in S phase, with a maximum at 24 h from paclitaxel administration. Administering paclitaxel, in graded doses, 15 min before a 10-Gy X-ray treatment resulted in a linear regression line, almost parallel to that with paclitaxel alone, with a growth delay of about 6 days. In contrast, varying the X-ray dose with a constant paclitaxel injection (45 mg/kg b.w.) treatment showed some degree of synergism as the linear regression curves diverged. Interval time and sequence between paclitaxel administration and a 10 Gy X-ray treatment did not influence TGD. Protocols with paclitaxel at 30, 45, or 60 mg/kg were combined with radiation treatments at various doses (from 10 to 65 Gy). Values of TCD50 varied from 50.8 Gy for X-ray alone to 31.8 Gy for paclitaxel 60 mg/kg + X-ray. No differences were observed among MDD of different protocols.

Conclusions: These results suggest that, under some conditions, paclitaxel combined with radiation can show superadditive effects and this result combined with the lack of severe normal tissue damage indicate that a favorable therapeutic gain can be obtained.     

Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids

The interaction between the estrogen receptor and a variety of flavonoids was studied in the presence or absence of estradiol using a stably-transfected human breast cancer cell line (MVLN). On the other hand, flavonoids were evaluated for their effects on proliferation in estrogen-dependent (MCF-7) and independent (MDA-MB231) human breast cancer cells. We established a relationship structure-activity and determined regions and/or substituents essential for estrogenic or antiestrogenic activities. In contrast, we did not find the same relationship for cell proliferation. Among all flavonoids used, only 7-methoxyflavanone and 7,8-dihydroxyflavone at high concentrations (50 μM) possess antiestrogenic and antiproliferative activities. These results suggest that two hydroxyls (in positions 7 and 8) or 7-methoxy substituents are essential for the antiestrogenic activity of flavonoids. However, it seems that flavonoids at high concentrations exert their antiproliferative activity through other estrogen receptor-independent mechanisms.     

A case of asynchronous development of transitional cell carcinoma in the bladder and renal pelvis after prolonged cyclophosphamide therapy

Urinary bladder cancers occurring after prolonged cyclophosphamide therapy are being increasingly reported. Cyclophosphamide-induced cancer in the upper urinary tract is not, however, generally recognized. We report a case of asynchronous development of transitional cell carcinoma in the bladder and renal pelvis, after prolonged cyclophosphamide therapy for non-Hodgkin's lymphoma. To date, at least 8 cyclophosphamide-related cancers have been reported in the upper tract. These cases are reviewed briefly.     

Metastasis to the iris in squamous cell lung cancer

A 72-year-old Japanese woman, suffering from squamous cell lung cancer with brain metastasis, underwent 2 courses of combination chemotherapy, consisting of cisplatin and vindesine. Although both the primary tumor and the brain metastasis regressed markedly, she developed left ocular pain with blurred vision. An abnormal mass was found in the left iris, and cytologic examination of the aqueous aspirate revealed a few malignant cells, which, when examined by electron microscopy, were considered to be derived from squamous cell carcinoma of the lung.     

Assessment of vascularity in breast carcinoma by computer-assisted video analysis (CAVA) and its association with axillary lymph node status

Case-control methodology was used to evaluate the significance of vascularity in small breast carcinomas with regard to the presence or absence of axillary lymph node metastases. Vascularity was assessed in 32 axillary node positive primary breast tumours (LN+ve) less than 2 cm in size and compared with 56 control axillary node negative primary tumours (LN–ve), which were matched for histological type and grade and tumour size. This study design employed computer-assisted video analysis (CAVA) to assess the total blood vessel perimeter (BVP), total blood vessel area (BVA), and total blood vessel density (BVD) throughout a tissue section that encompassed an entire cross section of the tumour and its immediate periphery. The BVA and BVD in these tumours were not significantly different between LN+ve and LN–ve groups. The LN–ve carcinomas had, on average, a significantly (P < 0.05) higher total BVP (3355 µm/mm²) than LN+ve tumours (2771 µm/mm²). 'Hot spot' areas were also independently assessed by two pathologists and the same areas measured by CAVA. A strong correlation (P < 0.001) between the two methods of assessment of BVD of the neovascular 'hot spots' was found; however, no association with axillary lymph node metastasis was found using either method of assessment. In conclusion, vascularity assessed by either blood vessel density or blood vessel size in primary invasive breast cancers less than 2 cm in diameter showed no association with axillary lymph node metastasis; in fact a negative association was found with total BVP of whole tumour sections and BVD in 'hot spots' using CAVA. Further, this study has established a computer-assisted method of quantifying vascularity in solid neoplasms and is a positive step towards a standardised approach to this diverse and methodologically variable area.     

Tumor-specific Activation of Mitogen-activated Protein Kinase in Human Colorectal and Gastric Carcinoma Tissues

To search for the signaling events in colorectal carcinoma relevant to its tumorigenesis, we investigated the activity of mitogen-activated protein kinase (MAPK) in human colorectal carcinoma tissues and paired normal tissues. Of 64 cases examined, approximately 75% (48 cases) showed tumor-specific activation of MAPK by in situ kinase renaturation assay, as well as in vitro kinase assay with immunoprecipitated MAPK. In addition, tumor-specific activation of MAPK was associated with the activation of MAPK kinase in the cases we examined. However, no clear correlation of MAPK activation with lymph node involvement, metastatic rate, stage, histological classification, age or sex was observed. These results suggest that the MAPK pathway is involved in colorectal tumor development, but its activation alone is not sufficient for malignant conversion. In contrast to colorectal carcinoma, gastric carcinoma tissues showed a lower rate of MAPK activation, suggesting that the signaling pathway activated in colorectal carcinoma tissues may differ in part from that of gastric carcinoma.     

Potentiation of Paclitaxel Cytotoxicity by Inostamycin in Human Small Cell Lung Carcinoma, Ms-1 Cells

In the present study, we found that inostamycin increased the ability of paclitaxel to induce apoptosis in Ms-1 cells. A considerably higher concentration of paclitaxel was required for the induction of apoptosis in Ms-1 cells than in other cell lines tested. Treatment of Ms-1 cells with inostamycin, an inhibitor of phosphatidylinositol (PI) synthesis, reduced the dosage of paclitaxel required to induce cell death by apoptosis. This effect of inostamycin is specific to Ms-1 cells, and inostamycin did not increase the cytotoxicity of other antitumor drugs such as adriamycin, vinblastine, methotrexate, cisplatin, etoposide, or camptothecin in Ms-1 cells. Addition of inostamycin to paclitaxel-treated cells caused a significant increase in the sub G1 peak, representing apoptosis, which was accompanied by a decrease in the G2/M peak seen in paclitaxel-treated Ms-1 cells, without affecting paclitaxel-inhibited tubulin depolymerization. Moreover, paclitaxel did not enhance inostamycin-inhibited PI synthesis. The expression levels of Bcl-2, Bax, and Bcl-X_L were not changed following the co-treatment with inostamycin plus paclitaxel, whereas the activated form of caspase-3 was markedly increased. Thus, inostamycin is a chemosensitizer of paclitaxel in small cell lung carcinoma Ms-1 cells.     

Linoleic acid and tumor necrosis factor-α increase manganese superoxide dismutase activity in intestinal cells

Manganese superoxide dismutase (MnSOD) protects mitochondria from oxidative damage. Alterations in the regulation of MnSOD plays an important role in the development of many types of cancer. Activity of this enzyme is induced by inflammatory cytokines and other conditions that increase oxygen radical production. High levels of dietary lipid have been shown to decrease MnSOD activity. This study was designed to define the effect of various type of fatty acids on MnSOD activity and MnSOD induction. IEC-6 cells were treated with 40 μmol/l of either linoleic acid (LA), eicosapentaenoic acid (EPA), or oleic acid (OA) in the presence or absence of 10 ng/ml tumor necrosis factor-α (TNF-α). Fatty acid supplementation increased MnSOD activity. MnSOD activity was greater in the LA group than in the EPA or OA groups. TNF-α induced MnSOD activity equally in all fatty acid-supplemented groups. High levels of MnSOD activity may be an indicator of chronic inflammation resulting from fatty acid, particularly LA, supplementation.     

可变数串联重复序列检测异基因外周血造血干细胞移植后植？…

目的 从血型、染色体核型、ＤＮＡ可变数串联重复序列（ＶＮＴＲ）几个方面进行对比研究以更好地评估异基因移植后的植入状态及其与疾病复发的关系。方法 采用聚合酶链反应（ＰＣＲ）方法扩增Ｄ１７Ｓ３０、Ｄ１Ｓ８０、ＡｐｏＢ３个不同位点的多态性,对１５例白血病患者异基因外周血造血干细胞移植（ａｌｌｏ－ＰＢＳＣＴ）后的嵌合状态进行检测,对其中７例异性间移植和３例血型不合移植又分别进行了染色体核型分析和全套血型分