bluuebunny/crossref_metadata_2025 huggingface dataset:
Peri‐tumor interleukin‐2 causes systemic therapeutic effect via interferon‐γ induction
Authors: Vaage Jan
Published: February 2007

This study compares the direct local therapeutic effects of multiple peri‐tumor injections of interleukin‐2 (IL‐2) and interferon gamma (IFN‐γ), also the associated systemic therapeutic effects on distant untreated tumors resulting from the peritumor injections. The therapeutic effects were tested against intramammary implants of an immunogenic, syngeneic C3H mammary carcinoma. Peritumor IL‐2 and IFN‐γ had nearly equal local and systemic therapeutic effects. In a comparison of the therapeutic effects of IL‐2 and IFN‐γ injected systemically, only the IFN‐γ injections resulted in a significant number of cures. IL‐2 and IFN‐γ did not have an additive effect when used in combination, suggesting that they have connected, rather than separate, paths of action in the anti‐tumor immune response. The injection of anti‐IFN‐γ‐MAb abrogated the systemic therapeutic effect of peri‐tumor IL‐2, indicating that the systemic therapeutic effect was the result of IFN‐γ induction at the IL‐2 injection site.
Multifactorial resistance in LS174T human colon carcinoma cells selected with doxorubicin
Authors: Rabier Mireille J. , Bruno Nicholas A. , Slate Doris L.
Published: February 2007

A series of doxorubicin‐resistant variants of the human LS 174T colon carcinoma cell line was generated by stepwise selection. These variants also exhibited increased resistance to vinblastine, etoposide, cis‐platinum, and melphalan, suggesting that resistance was multifactorial. The parental LS 174T cell line and 3 resistant variants were examined for over‐expression of P‐glycoprotein, changes in total cellular glutathione content, and the level of topoisomerase‐II expression. Changes in all of these parameters were observed in the doxorubicin‐selectants, along with a marked shift in the intracellular distribution of doxorubicin. P‐glycoprotein RNA and protein levels were increased 2‐ to 3‐fold in the resistant variants, while total glutathione levels increased 1.4‐ to 2.1‐fold. Treatment with DL‐buthionine‐[S,R]‐sulfoximine, an inhibitor of glutathione biosynthesis, was able to reverse resistance to cis‐platinum and melphalan in these variants, but had little effect on doxorubicin resistance. Immunoblot analysis of cell extracts indicated that the level of DNA topoisomerase II (EC 5.99.1.3) in the doxorubicin‐resistant LS174T cells was decreased by approximately 50% compared with the parental cell line. Doxorubicin was mainly localized to the cytoplasm in resistant cells, while in the parent line it was mostly found in the nucleus. This constellation of changes suggests that selection with doxorubicin activated several mechanisms of resistance involving drug transport, metabolism, and ability to reach nuclear target sites.
Improvement by affinity chromatography on antiidiotypic monoclonal antibodies (MAbs) of immunoreactivity and in vivo targeting of radiolabelled anti‐HMW‐MAA MAb TP61.5 in nude mice bearing human melanoma lesions
Authors: Temponi Massimo , Fawwaz Rashid A. , Kekish Ulana , Wang Theodore S. T. , Ferrone Soldano
Published: February 2007

The human high‐molecular‐weight melanoma‐associated antigen (HMW‐MAA) represents a useful marker for immunoscin‐ tigraphy in patients with melanoma. Since injection of a radiolabelled anti‐HMW‐MAA monoclonal antibody (MAb) visualizes only about 60% of melanoma lesions, approaches are being developed to increase the sensitivity of immunoscintigraphy. One of them aims at improving the immunoreactivity of radiolabelled anti‐HMW‐MAA MAbs, since this approach may improve the targeting of radiolabelled MAbs to melanoma lesions. We have previously shown that affinity chromatography on insolubilized anti‐idiotypic MAbs is a useful method for purifying immunoreactive anti‐HMW‐MAA MAb TP61.5 from 125I‐la‐ belled MAb preparations and that not all the anti‐idiotypic MAbs are useful for this purpose. Since the increasing number of available anti‐idiotypic MAbs is likely to facilitate the application of this procedure in many antigenic systems, we have now tested criteria to select anti‐idiotypic MAbs suitable for the purification procedure. Furthermore, we have investigated the effect of the increase in immunoreactivity of 125I‐MAb TP6 1.5 on its in vivo targeting to human melanoma lesions transplanted into nude mice. Among the 3 anti‐idiotypic MAbs tested, the most effective in purifying immunoreactive MAb TP6 1.5 mole cules following radiolabelling is MAb TK7‐110, with which 125I‐MAb TP61.5 displays an immunoreactivity similar to that displayed with melanoma cells. This parameter may represent a useful criterion to identify anti‐idiotypic MAbs suitable for the purification procedure, if the present results are confirmed with a large number of anti‐idiotypic MAbs in different antigenic systems. We have also shown that an incubation time for up to 4 hr of 125I‐MAb TP61.5 with insolubilized MAb TK7‐110 is the most effective in increasing immunoreactivity and in recovering immunoreactive MAb applied to the affinity matrix. The increase in the immunoreactive fraction of 125I‐MAb TP61.5 significantly increases its specific localization in human melanoma lesions transplanted into nude mice. These results suggest that purification of radiolabelled immunoreactive anti‐HMW‐ MAA MAb TP61.5 by affinity chromatography using antiidiotypic MAb TK7‐110 represents a useful approach to increasing the sensitivity of immunoscintigraphy in patients with melanoma.
Cancer mortality in the ussr, 1986‐88
Authors: La Vecchia Carlo , Levi Fabio , Lucchini Franca , Evstifeeva Tatiana , Boyle Peter
Published: February 2007

Mortality rates in the USSR for the major cancer sites have been computed for the period 1986‐88 from official numbers of certified deaths and population estimates provided by the World Health Organization databank, and compared with rates for 26 other European countries. Among males, elevated mortality rates (age‐adjusted, world standard) were observed for cancer of the oral cavity and pharynx (6.6/100,000), oesophagus (8.4/100,000) and larynx (6.8/100,000). Mortality from cancer of the stomach (38.4/100,000 males and 16.5/100,000 females, for a total of 87,000 deaths per year) was the highest in Europe. Likewise, overall lung cancer rates among males (61.0/100,000, for over 77,000 deaths per year) were among the highest in Europe, and showed substantial rises over the last 2 decades. Lung cancer mortality in females was comparatively low (6.9/100,000), and increased only moderately. Rates for cancers of the intestine (14.6/100.000 males and 10.6/100,000 females) and of the female breast (12.9/100,000) were comparatively low as compared to most other European countries, and those for prostatic cancer (5.9/100,000) were the lowest registered in Europe. In contrast, mortality for cancer of the uterus (9.7/100.000) was among the highest in Europe, probably due to high mortality from cervical cancer. Priorities for cancer control in the Soviet Union are thus reduction of consumption of tobacco and alcohol, which largely explain the high rates for lung and upper digestive and respiratory sites, improvements in diet composition and food storage to reduce the substantial excess of stomach cancer, and rational screening for cervical cancer.
Expression of lactoferrin in human stomach
Authors: Luqmani Y. A. , Campbell T. A. , Bennet C. , Coombes R. C. , Paterson I. M.
Published: February 2007

The expression of the haeme‐binding protein, lactoferrin, was studied in human gastric tissues displaying normal, benign hyperplastic or malignant histology. A single 2.5‐kb mRNA was detected in only 14% (2/14) of normal resections. This was similar to the finding that 85% of tumours were also negative, with 4/27 positive. In contrast, samples with superficial or atrophic gastritis had a high frequency of expression, with 5/7 and 9/14 positive respectively. The higher incidence of lactoferrin mRNA in antral samples was a reflection of the greater proportion of these compared with body resections of patients with gastritis. No expression was seen in any of 5 gastric carcinoma cell lines. High levels were observed in the cardia, in contrast to complete absence in the oesophagus. Immunocytochemistry showed localization of lactoferrin in cells of both antral and body glands. Chief cells, but not adjacent parietal cells, were strongly stained. In tissues exhibiting superficial or atrophic gastritis we observed a greater degree and intensity of staining as compared with samples with normal histology. We also observed some staining of tumour cells, though this was very patchy. Lactoferrin may have a role in mucosal iron transport in both normal and highly proliferating tissue, but does not appear to be significantly associated with malignant lesions.
P‐glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines
Authors: Lai Gi‐Ming , Chen Yi‐Nan , Mickley Lyn A. , Fojo Antonio T. , Bates Susan E.
Published: February 2007

Four human colon cancer cell lines (SW620, LS 180, DLD‐I, and HCT‐15) and Adriamycin‐resistant sub‐lines with varying degrees of P‐glycoprotein expression were studied to evaluate the reversibility of Adriamycin resistance in human colon cancer. Two groups of cell lines were studied. In the first, including a series of Adriamycin‐resistant SW620 and DLD‐I sub‐lines, and in parental HCT‐15 cells, P‐glycoprotein has a major role in Adriamycin resistance, as evidenced by a correlation between Adriamycin resistance, expression of the multi‐drug‐resistance gene mdr‐I and its product, P‐glycoprotein (Pgp), decreased drug accumulation and reversibility by verapamil. In these cell lines, increasing doses of verapamil are required to fully reverse increasing levels of resistance. In the second group, including parental SW620, DLD‐I and LS 180 cells and Adriamycin‐selected LS 180 sub‐lines, P‐glycoprotein does not have a major role in Adriamycin resistance. There was correlation between the schedule dependence of Adriamycin cytotoxicity and the role of P‐glycoprotein in modulating reristance. In the cell lines in which P‐glycoprotein was a major determinant of Adriamycin resistance, the drug exposure (defined as the product of the concentration and the time of treatment) needed to achieve a given percent cell kill was reduced as much as 9‐fold when cells were treated for 7 days as compared with 3 hr. By comparison, in cell lines in which P‐glycoprotein played a lesser role, the drug exposure necessary to achieve a given percent kill increased under conditions of continuous treatment. In some human colon carcinoma cell lines Pgp appears to play a significant role in resistance to Adriamycin, and this can be overcome by the use of competitive inhibitors of Pgp. The increased sensitivity with continuous treatment observed in cell lines with P‐glycoprotein‐mediated resistance suggests that administration of drugs by continuous infusion may be valuable in reversing clinical drug resistance mediated predominantly by P‐glycoprotein.
Comparison of autocrine mechanisms promoting motility in two metastatic cell lines: Human melanoma and ras‐transfected NIH3T3 cells
Authors: Seiki Motoharu , Sato Hiroshi , Liotta Lance A. , Schiffmann Elliott
Published: February 2007

Tumor‐cell migration plays an essential role in invasion into surrounding tissues and the formation of metastatic colonies in distant organs. Metastatic human A2058 melanoma and ras‐ transfected NIH3T3 cells produce autocrine motility factors (AMFs) which stimulate their own motility, and the A2058 cell AMF (AMF/A2058) has been purified. In this study, we partially purified the AMF produced by N‐ras‐transfected NIH3T3 cells (AMF/NIH3T3) and compared it with AMF/A2058. The two AMFs differed in their gel filtration patterns and heat stability, although both elicited migration of N‐ras‐transfected NIH3T3 cells. The receptor for AMF/A2058 in A2058 cells is linked to pertussis‐toxin‐sensitive GTP‐binding protein. Pre‐treatment of N‐ras‐transfected NIH3T3 cells with pertussis toxin also specifically blocked the promotion of motility by AMF/A2058, but did not affect the activity of AMF/NIH3T3. Stimulation of N‐ras‐transfected NIH3T3 cells by both AMFs elicited an additive response. Thus, the autocrine mechanisms of these two metastatic tumor cell lines are different with regard to the AMF molecules, receptors, and signal transduction pathways.
Increased growth adaptability to 5‐fluorouracil and methotrexate of HT‐29 sub‐populations selected for their commitment to differentiation
Authors: Lesuffleur Thécla , Kornowski Anne , Augeron Chantal , Dussaulx Elisabeth , Barbat Alain , Laboisse Christian , Zweibaum Alain
Published: February 2007

Adaptation of the heterogeneous human colon carcinoma cell line HT‐29 to lethal concentrations of methotrexate (MTX) and 5‐fluorouracil (FUra) was shown to result in the emergence of sub‐populations of cells all stably committed to differentiation. It was postulated that these populations result from selection of a few cells present in the parental line which possess, associated with their ability to differentiate, particular advantages allowing them to adapt to adverse conditions such as MTX or FUra. The purpose of the present study was to further verify this hypothesis by investigating whether HT‐29 sub‐populations selected for the commitment of all cells to differentiation would spontaneously be more resistant and adaptable than the parental cells to MTX and FUra. This study included a mucus‐secreting clone (HT29‐16E), a transporting clone (HT29‐19A), and an enterocytic population selected by glucose deprivation (HT29‐Glc−/+). Although all 3 populations show only a slight increase in their spontaneous resistance to both drugs, as substantiated by the values of IC50, which are only less than 2‐fold higher than in parental cells, they are more adaptable as judged by growth curves, over a 50‐day culture period, under exposure to I μM FUra and 0.1 μM MTX. In sharp contrast to parental cells, which, at these concentrations, show a high rate of mortality, all 3 populations, although growing slowly, reach densities more or less close, depending on the drug and population concerned, to that of control untreated cells. These results show that, within population of cells of the same genetic origin, cells selected for their commitment to differentiation are more resistant and more adaptable to FUra and MTX than the parental population, which contains a majority (> 95%) of cells unable to differentiate.
The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors
Authors: Mizoguchi H. , Komiyama S. , Matsui K. , Hamanaka R. , Ono M. , Kiue A. , Kobayash M. , Shimizu N. , Welgus H. G. , Kuwano M.
Published: February 2007

Three cancer cell lines, IMC‐2, IMC‐3 and IMC‐4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC‐2 in nude mice was markedly faster than that of the IMC‐3 and IMC‐4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC‐2 cells in response to EGF, but no change for IMC‐3 and IMC‐4 cells. We examined response to EGF of IMC‐2 cells with regard to expression of a growth‐related oncogene (c‐fos), proteinases and their inhibiton. Expression of c‐fos was transiently increased in IMC‐2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase‐type plasminogen activator and 72‐kDa type‐IV colla‐genase in IMC‐2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor‐I (PAI‐1) and tissue inhibitor of metalloproteinases‐1 (TIMP‐1) in IMC‐2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.
Active oxygen transforms murine myeloid progenitor cells in vitro
Authors: Crawford Dana R. , Greenberger Joel S.
Published: February 2007

Active oxygen (AO) is ubiquitous in nature and its many forms can act as natural carcinogens. Their effect on the transformation of a mouse myeloid progenitor cell line was studied using anchorage‐independent colony formation in methylcellulose as the primary assay. Both cytotoxic and non‐toxic concentrations of t‐butylhydroperoxide, hydrogen peroxide and menadione were examined. At non‐cytotoxic concentrations, no AO transformation of these cells from interleukin‐3 dependence to factor independence (FI) was observed, even after as many as 25 treatments. At cytotoxic concentrations, however, all 3 classes of AO transformed the cells to FI growth. The most potent agent was t‐butyl hydroperoxide (43‐fold induction), followed by hydrogen peroxide and then menadione. As little as one exposure to cytotoxic levels of these oxidants induced significant transformation, with relative potencies the same as those observed for multiple exposures. These inductions were not due to general cytotoxic effects, since sodium fluoride and heat‐shock treatment gave minimal inductions. AO‐induced colonies in methylcellulose that were removed, examined and then injected into pre‐irradiated mice uniformly produced tumors. Control, non‐treated cells did not form tumors. Tumorigenic cells did not form colonies in methylcellulose at lower plating densities. Furthermore, low numbers of transformed cells supplemented to high density with normal cells showed a small but insufficient increase in colony number as compared with high‐density cultures of transformed cells. Our results suggest that the transformants depend upon a paracrine mechanism of growth that is mediated by the transformed cells. Studies on selected factor‐dependent cell lines and antibodies to interleukin‐3, interleukin‐4, granulocyte‐macrophage‐ and macrophage‐colony stimulating factors, suggest that this putative paracrine factor is unique.
Human tumor spontaneous metastasis in immunosuppressed newborn rats. II. Multiple selections of human melanoma metastatic clones and variants
Authors: Bailly Maryse , Doré Jean‐François
Published: February 2007

Using a recently developed model of human tumor spontaneous metastasis in immunosuppressed newborn rats, we selected variants with different metastatic abilities from the human melanoma cell line M4Be. We used 4 in vivo selection approaches, by direct serial tumor transplantations or by techniques involving in vitro reculture of the cells recovered from S.C. tumors or lung and lymph‐node metastases. In addition, 3 series of clones were derived in vitro from the M4Be cell line, either by limiting‐dilution or by cloning in semi‐solid agar and harvesting small and large colonies. A considerable amount of heterogeneity in tumorigenicity and metastatic ability was demonstrated among variants and clones following in vivo selections and in vitro cloning. Four main malignant phenotypes were identified among those expressed by the selected cells: poorly tumorigenic and poorly metastatic; poorly tumorigenic and highly metastatic; highly tumorigenic and poorly metastatic; and highly tumorigenic and highly metastatic. However, while malignant pheno‐type (i.e., tumorigenicity and metastatic ability) did not appear to be grossly influenced by in vitro cloning procedure, it appeared greatly influenced both by the in vivo selection procedure (direct transplantations or use of in vitro culture between the in vivo passages) and by the origin of the cells under selection (S.C. tumor or metastases). Our study provided us with a large panel of variants and clones with varying metastatic abilities, which represent a model of human melanoma spontaneous metastasis allowing the study of critical determinants in human tumor metastasis.
The role of alkaline reflux in esophageal carcinogenesis induced by N‐amyl‐N‐methylnitrosamine in rats
Authors: Seto Yasuyuki , Kobori Oichiro , Shimizu Toshio , Morioka Yasuhiko
Published: February 2007

It is now accepted that the incidence of esophageal carcinoma is highest in the middle thoracic region. Esophageal carcinoma after gastrectomy, however, has a tendency to develop in the lower thoracic region. These studies suggest a possible correlation between the development of esophageal carcinoma and gastrectomy, i.e., alkaline reflux into the esophagus. To elucidate this correlation, the role of alkaline reflux of duodenal contents in the development of esophageal squamous‐cell carcinoma induced by N‐amyl‐N‐methylnitrosamine (AMN) was investigated in Wistar rats. The animals were divided into 3 groups; gastrectomized rats with or without regurgitation of duodenal contents into the esophagus, and control rats without gastrectomy. All received low doses of AMN for 8 weeks and were subsequently killed for pathological examination. Esophageal squamous‐cell carcinomas were found only in gastrectomized rats with regurgitation. The carcinomas were found exclusively in areas of reflux esophagitis and were accompanied by severe dysplasia. Our results indicate that alkaline reflux of duodenal contents strongly contributes to the development of esophageal squamous‐cell carcinoma.
Infection of rats with HTLV‐1: A small‐animal model for HTLV‐1 carriers
Authors: Suga T. , Kameyama T. , Kinoshita T. , Shimotohno K. , Matsumura M. , Tanaka H. , Kushida S. , Ami Y. , Uchida M. , Uchida K. , Miwa M.
Published: February 2007

A human T‐cell line producing human T‐cell leukemia virus type 1 (HTLV‐1), MT‐2, was injected intravenously into female F344 rats aged 5 weeks to make HTLV‐1 carrier rats. Antibody against HTLV‐1 was detected at the 5th week after MT‐2 injection, and its titer reached a high plateau which continued from the 15th to the 27th week. The antibodies were against p 19, p24, p28 and p53 of HTLV‐1 antigens from MT‐2 cells. The gag, pX and LTR nucleotide sequences of HTLV‐1 provirus were demonstrated by using polymerase chain reaction (PCR) in the peripheral‐blood mononuclear cells of 3 rats at the 44th week and 2 at the 66th to 68th week out of 8 F344 rats injected with MT‐2 cells. Quantification of the HTLV‐1 proviral sequence revealed that 30 to 60 molecules were present in 105 peripheral‐blood mononuclear cells, indicating that the rats were chronically infected with HTLV‐1. HTLV‐1‐infected rats could serve as a small‐animal model for studying the pathophysiological state of HTLV‐1 carriers and also that of HTLV‐1 infection on various HTLV‐1‐related diseases, including adult T‐cell leukemia and HTLV‐1‐associated myelopathy.
Modulation of tumoricidal activity, induced in bone‐marrow‐derived mononuclear phagocytes by interferon γ or Corynebacterium parvum, by interferon β, tumor necrosis factor, prostaglandin E2, and transforming growth factor β
Authors: Keller Robert , Keist Ruth , van der Meide Peter H.
Published: February 2007

Among a series of agents, including various interleukins and growth factors, only interferon γ (IFNγ) and heat‐killed Corynebacterium parvum (CP) organisms were able to elicit, within 24 hr, tumoricidal activity in bone‐marrow‐derived mononuclear (BMM) phagocytes. In subsequent experiments, the abilities of interferon β (IFNβ), tumor necrosis factor α (TNFα), prostaglandin E2 (PGE2), and transforming growth factor β (TFGβ), alone or in combinations of 2, to modulate tumoricidal activity triggered in BMM phagocytes by IFNγ or CP, were compared. In concentrations secreted by macrophages under physiological conditions, these agents proved potent in modulating induction and/or expression of tumoricidal activity. However, their ability to interfere with tumoricidal activity varied considerably, depending on the extent of macrophage differentiation and/or functional responsiveness, the pathway of macrophage activation, the type, concentration and combination of the macrophage secretory molecules, and on whether the agents were present during induction and expression or only during expression of tumoricidal activity. In showing that IFNβ and TNFα were mostly enhancing and TGFβ mostly suppressive, whereas PGE2 suppressed induction but enhanced expression of tumoricidal activity, our findings provide further support for the concept that these macrophage‐derived molecules have a key role in autocrine regulation of macrophage functional activities.
Neutral glycosphingolipid expression in B‐cell neoplasms
Authors: Kalisiak Angela , Minniti J. Gerald , Oosterwuk Egbert , Old Lloyd J. , Scheinberg David A.
Published: February 2007

The expression of neutral glycosphingolipids (GSL) in 37 B‐cell neoplasms [7 acute lymphocytic leukemia (ALL), 5 Burkitt's lymphoma (BL), 7 chronic lymphocytic leukemia (CLL), 5 diffuse, poorly differentiated lymphoma (DPDL), 6 diffuse histiocytic lymphoma (DHL), 3 hairy‐cell leukemia (HCL), and 4 multiple myeloma (MM)] was examined. Patterns of expression of simple (GlcCer, LacCer) and globo‐series GSL (Gb3, Gb4,) were found for each tumor type. In addition, pre‐B ALL expressed the neo‐lacto series GSL, paragloboside, which was not significantly seen at later stages of maturation. As a group, leukemias expressed about 10 times higher ratios of simple GSL to Globo‐series GSL as compared to lymphomas, regardless of stage of differentiation. Significant amounts of GSL of other series were not found except in one CLL which contained asialo‐GM2. GSL phenotype in these cells was not grossly affected by cell genotype since pre‐B ALL containing Philadelphia chromosome t(9q;22q) translocations were similar to other ALL; and DHL with t(8q;14q) translocations had GSL patterns similar to other DHL samples and dissimilar to GSL patterns found in Burkitt's lymphomas with t(8q;14q). Differences in GSL expression among the different types of B‐cell neoplasm suggested that GSL patterns form a phenotypic map that may complement the traditional glycoprotein immunophenotypic map and contribute to our understanding of the biology of these diseases and B‐cell differentiation.
PCR‐detected genital papillomavirus infection: Prevalence and association with risk factors for cervical cancer
Authors: Rohan Thomas , Mann Valerie , McLaughlin John , Harnish Delsworth G. , Yu He , Smith David , Davis Ruth , Shier R. Michael , Rawls William
Published: February 2007

In an investigation conducted in student health clinic patients, the polymerase chain reaction was used to detect human papillomavirus (HPV) DNA, thereby allowing measurement of the prevalence of HPV infection and study of the association between HPV infection and risk factors for cervical cancer. Of 159 women eligible to participate, 105 (66%) provided specimen of cervical cells for HPV typing, and also answered an interviewer‐administered questionnaire which sought information on risk factors for cervical cancer. Nucleic acid extracted from cervical cells was screened with primers for HPV types 6, 11, 16, 18, 33 and with an HPV Consensus primer. Overall, the prevalence of HPV infection was 18.1%, while for HPV‐6/11 it was 2.9% and for HPV‐16/18 it was 10.5%. There were statistically significant increases in risk of HPV infection with history of ever having smoked cigarettes (overall, and for HPV‐16 alone) and with a history of usually having sexual intercourse during menstrual periods (overall, but not for HPV‐16), and these associations were independent of the effects of age at first sexual intercourse and number of sexual partners. The latter 2 variables, as well as the total number of occasions of sexual intercourse, a history of anal intercourse, and a history of ever having used oral contraceptives, were not associated with statistically significant alterations in risk of HPV infection.
The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis
Authors: Auborn Karen J. , Woodworth Craig , Dipaolo Joseph A. , Bradlow H. Leon
Published: February 2007

Cancer of the genital tract is the final outcome of some infections with human papillomavirus (HPVs), and the most estrogen‐sensitive cells are at greatest risk for the HPV‐related cancers. Therefore we investigated relationships between HPVs and estrogen metabolism in cells of the genital tract. Increased conversion of estradiol to 16α‐hydroxyestrone, known to be a risk factor for cancer in some other estrogen‐sensitive cells, was investigated in keratinocytes from the genital tract. Primary cells, particularly those explants from the transformation zone of the cervix, are able to 16α‐hydroxylate estradiol. Both cervical and foreskin cells immortalized with HPV‐16 are greatly enhanced in the 16αa‐hydroxylation of estradiol as compared with normal cells. We suggest a model whereby the combined action of 16α‐hydroxylation of estrogen and HPV work together to promote cell proliferation.
Prognostic scores combining clinical, histological and morphometric variables in assessment of the disease outcome in female breast cancer
Authors: Aaltomaa S. , Lipponen P. , Eskelinen M. , Kosma V‐M. , Marin S. , Alhava E. , Syrjänen K.
Published: February 2007

Clinical features, 8 histological features, 7 nuclear morphometric variables and 2 mitotic indices were entered in a Cox's model to assess their independent predictive power in a series of 517 breast cancer patients followed up for over 10 years. The volume‐corrected mitotic index (M/V index) (p< 0.001), axillary lymph‐node status (p= 0.002), the shortest nuclear axis (p= 0.006) and the degree of tubule formation (p= 0.02) predicted independently the recurrence‐free survival. In N−tumours (n = 293), the M/V index (p= 0.005), the degree of tubule formation (p= 0.016) and tumour size (p= 0.023) were independent prognostic predictors, whereas in N+tumours (n = 224), only the M/V index (p= 0.004) and the maximum nuclear axis (p= 0.004) had independent prognostic value. The corrected survival was predicted independently by the axillary lymph‐node status, degree of tubule formation, M/V index, tumour size (p< 0.001), age (p= 0.002) and year of treatment (p= 0.008). In N−tumours, the degree of tubule formation (p= 0.005) and intraductal growth pattern (p = 0.015) exhibited independent predictive value. In N+tumours, patient survival was related to the M/V index (p< 0.001), tumour size (p= 0.005) and patient age (p= 0.005). The results show that the assessment of the M/V index, axillary lymph‐node status, tumour size, intraductal growth pattern and tubule formation are reliable factors in predicting the prognosis of breast cancer. The conventional mitotic activity index (MAI) and histological grading should be replaced by the M/V index in histological assessment of malignancy in breast cancer. The prognostic scores combining the independent variables reflecting the proliferative rate and metastatic potential of the tumours are more accurate predictors of the recurrence‐free survival and overall survival (p< 0.0001) than the single variables used alone.
Humoral immune response in disease‐free advanced melanoma patients after vaccination with melanoma‐associated gangliosides
Authors: Portoukalian Jacques , Carrel Stefan , Doré Jean‐François
Published: February 2007

Several studies have shown that melanoma‐associated gangliosides are immunogenic in melanoma patients and that antibodies against them have a favorable prognostic effect. Our study aims at characterizing the humoral immune response in disease‐free, advanced melanoma patients vaccinated with a total ganglioside fraction extracted from pooled metastases of human melanoma, containing as major gangliosides GM3 and GD3, and as minor ones GM2 and GD2. Prior to vaccination, all patients were made disease‐free by surgical removal of skin, lymph‐node or other distant metastases. Repeated vaccinations were carried out intradermally with gangliosides either in the native form in buffered solution, or in the form of liposomes. Serum samples were collected at regular intervals and assayed by ELISA for the presence of specific IgG and IgM antiganglioside antibodies. Selected samples were tested by immunostaining on thin‐layer plates to specify the ganglioside species involved in the reactivity. Out of 32 evaluable patients, 17 presented a significant increase in antibody titer, mostly of the IgG isotype, which was maximal between 2 and 4 months after starting injections of gangliosides, and gradually disappeared within 1 year. No significant difference could be seen between the group of 20 patients treated with native gangliosides and the group of 12 vaccinated with the gangliosides in liposomes. All gangliosides seemed to be immunogenic, but GM2 and GD2 were somewhat more reactive. The disease‐free intervals for the patients who showed an antibody response to the treatment were significantly higher (p < 0001) than those of the non‐responding group, as compared by the Kaplan‐Meier method.
Estrogen inhibition of MPA‐Induced mouse mammary tumor transplants
Authors: Kordon Edith , Lanari Claudia , Molinolo Alfredo A. , Elizalde Patricia V. , Charreau Eduardo H. , Pasqualini Christiane Dosne
Published: February 2007

Estrogen compounds were used to treat mice bearing syngeneic transplants of medroxyprogesterone acetate(MPA)‐induced BALB/c mammary adenocarcinomas. Both MPA‐dependent and MPA‐independent tumor lines were used. These lines expressed estrogen (ER) and progesterone receptors (PR). We demonstrate that different doses of estradiol benzoate (EB) and 17‐β‐estradiol (E2) inhibit tumor growth and induce tumor regression in both MPA‐independent and ‐dependent tumors, even in the presence of MPA or progesterone (P). EB was unable to induce regression of (ER‐) hormone‐independent tumor lines. A few MPA‐dependent tumors became resistant to the estrogenic treatment; in subsequent passages some of these tumors retained their MPA‐responsiveness, although estrogen sensitivity was not recovered.
Differential mRNA levels of c‐myc, c‐fos and MHC class I in several clones of a murine fibrosarcoma
Authors: Gaforio J. J. , Pérez M. , Algarra I. , Mialdea M. J. , Ljunggren H. G. , Garrido F.
Published: February 2007

We have evaluated the relationship between MHC class‐I, c‐myc and c‐fos proto‐oncogene expression in several clones of a methylcholanthrene‐induced fibrosarcoma (GR9) which originated in a BALB/c mouse. These clones represent a heterogeneous population and differ markedly with regard to H‐2 class‐I cell‐surface expression, local tumor growth, NK sensitivity and metastatic potential. In the present study we show that cell‐surface expression of MHC class‐I antigens correlates inversely with levels of c‐myc mRNA transcripts, On the other hand, mRNA levels of c‐fos are correlated directly with the amount of mRNA of MHC class I. Treatment of the B9 clone with gamma interferon increased mRNA transcription and surface expression of H‐2 class‐I antigens, while c‐myc transcription was simultaneously down‐regulated. In contrast, c‐fos mRNA levels remained unaltered.
Tumor‐cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small‐cell lung carcinoma
Authors: Brezicka Fred‐Thomas , Holmgren Jan , Kalies Inge , Lindholm Leif
Published: February 2007

Monoclonal antibodies (MAbs) reactive with the ganglioside fucosyl GM1 (Fuc‐GM1), an antigen associated with small‐cell carcinoma of the lung (SCLC), were tested for their ability to mediate tumor‐cell killing in vitro in conjunction with humoral and cellular effectors and to inhibit tumor engraftment in nude mice in vivo. MAbs F12 and F15, both IgG3k, induced human complement‐mediated cytolysis of 3 Fuc‐GM1‐expressing tumor cell lines: one rat hepatoma cell line, H4‐II‐E, and 2 human SCLC cell lines, NCI H69 and NCI H128. F12 and F15 also induced ADCC of these cell lines in the presence of either murine or human effector cells. Addition of sub‐cytolytic amounts of fresh human serum as complement source resulted in enhanced ADCC induced by MAb F12 (IgG3). Also a Fuc‐GM1‐reactive MAb of IgM isotype, F9, was able to induce such complement‐aided ADCC (CADCC). F12 and F15 both proved to effectively inhibit engraftment of H4‐II‐E tumors in nude mice. A single dose of a modest amount (40 μg) of MAb conferred 65 to 100% protection against development of tumors. Our results demonstrate that Fuc‐GMI can act as a target antigen on tumor cells for specific immunotherapy in vitro and in a mouse model in vivo. Complement and murine and human mononuclear effector cells were effective mediators of tumor cytolysis in vitro in the presence of murine Fuc‐GM1‐reactive MAbs. Our results also suggest that humoral and cellular effectors may co‐operate in specific tumoricidal reactions and that these may be induced by antibodies of both IgG and IgM isotypes.
Association between restriction fragment length polymorphism of the L‐myc gene and lung metastasis in human breast cancer
Authors: Champeme Marie‐Hélène , Bieciie Ivan , Latil Alain , Hacene Kamel , Lidereau Rosette
Published: February 2007

EcoRI restriction fragment length polymorphism (RFLP) of the L‐myc gene was examined in leukocyte DNAs isolated from 381 breast cancer patients. No differences in the patterns of L‐myc RFLP were found between breast cancer patients and healthy individuals. However, among 97 patients who relapsed, a statistical correlation was found between L‐myc RFLP and lung metastases (p < 0.05). These results are in close agreement with previous findings in patients with cancer of the lung, bone or kidney, and suggest that L‐myc RFLP may be a useful marker for predicting lung metastasis in some human cancers.
Genital papillomavirus infection and cervical dysplasia—opportunistic complications of hiv infection
Authors: Laga Marie , Icenogle Joseph P. , Marsella Richard , Manoka Abib Thiam , Nzila Nzilambi , Ryder Robert W. , Vermund Sten H. , Heyward William L. , Nelson Ann , Reeves William C.
Published: February 2007

Certain human genital papillomaviruses (HPV) are strongly associated with cervical dysplasia and cancer. Evidence is accumulating that HPV infection and ano‐genital cancers are more common in patients with the acquired immunodeficiency syndrome. The objective of our study was to evaluate the extent to which HPV infection and associated cervical disease constitute opportunistic complications of human immunodeficiency virus (HIV) infection in a population of sexually promiscuous, HIV‐infected women in Kinshasa, Zaire. In 1989 we obtained Pap smears and cervicovaginal lavage specimens for HPV DNA testing from 47 HIV‐seropositive and 48 HIV‐seronegative prostitutes who were part of a cohort under observation since 1988. Thirty‐eight percent of the HIV‐seropositive and 8% of the seronegative women (odds ratio = 6.8; p = 0.001) had HPV DNA detected by either Vira Type, a dot‐blot assay which detects specific genital HPV types, or low‐stringency Southern blot, which detects all HPV types. Eighty‐two women (86%) had an interpretable Pap smear; 11 of 41 (27%) HIV‐seropositive women and one of 41 (3%) seronegative women had cervical intra‐epithelial neoplasia (CIN) (odds ratio = 14.7; p = 0.002). HIV seropositivity, HPV infection and CIN were highly associated. Eight (73%) of 11 seropositive women with CIN had HPV detected. Both HPV infection and cervical cancer may emerge as opportunistic complications of HIV infection in populations in which HIV, HPV and cervical cancer are common.
Quantitative dot blot analyses of blood‐group‐related antigens in paired normal and malignant human breast tissues
Authors: Ura Yasuaki , Dion Arnold S. , Williams Charlene J. , Olsen Brian D. , Redfield Ernest S. , Ishida Masao , Herlyn Meenhard , Major Pierre P.
Published: February 2007

Membranes were prepared from 31 breast‐cancer specimens and adjacent mammary tissues, dot‐blotted to nitrocellulose paper, and reacted with monoclonal antibodies (MAbs) (A, B, Lewis a, Lewis b, sialylated Lewis a, Lewis x, and Lewis y) and lectins (Ulex europaeus, peanut agglutinin) having various blood‐group specificities. The expression of epithelial membrane antigen was assayed with MAb MA5. The ratio of breast‐cancer to normal mammary membrane preparations (C/N ratios) of these reagents was measured by densitometric scanning. We observed a decrease in the levels of A, B, Lewis a, Lewis b, sialylated Lewis a, and Lewis y antigens and an increase of Lewis x, T, and MAS‐reactive determinants in breast cancers. The incidence of incompatible A, as well as A and B, antigens was demonstrated for 2 patients of blood group B and O respectively. When the receptor content was plotted against the C/N ratio of these various reagents, a significant inverse relationship between the C/N ratio of Lewis x antigen and estrogen (ER) and progesterone receptor (PR) content was observed in breast cancers. The mean C/N ratio of Lewis x antigen was significantly higher in the ER‐negative/PR‐negative (ER−/PR−; 2.33 ± 1.17), as compared with the ER‐positive/PR‐positive (ER+/PR+; 0.97 ± 0.80). According to these observations, Lewis x antigen expression may be influenced by hormonal stimuli such as estrogen and progesterone.
Immunologic aspects of fibrosis in mouse mammary carcinomas
Authors: Vaage Jan
Published: February 2007

The nature of the fibrosis associated with mammary carcinomas MC2 and MC3 was investigated in syngeneic C3H mice. Accelerated and enhanced peri‐tumor cellular and fibrotic responses and retarded tumor growth were observed in actively immunized and in adoptively immunized mice, and in mice treated with IL‐2. T lymphocytes and, particularly, macrophages were closely associated with collagen deposition at the tumors. The collagen deposition frequently resulted in the encapsulation and regression of the less invasive tumor MC2. A cellular fibrous response was not observed at tumors implanted into athymic C3Hnu/nu mice. The results suggest that tumor fibrosis may in some circumstances be promoted by an immune response.
Altered prolactin response of the lymphocytes of tumor‐bearing mice
Authors: Biswas Ratna , Chattopadhyay Utpala
Published: February 2007

Interaction of prolactin and glucocorticoid on thymocytes and splenocytes of normal and tumor‐bearing mice with reference to their mitogen‐responsive blastogenesis has been studied. Prolactin alone had little or no mitogenic effect on thymocytes and splenocytes of normal mice but it was co‐stimulatory, with ConA, in inducing blastogenesis in normal splenocytes. Thymocytes and splenocytes of tumor‐bearing mice responded differently to prolactin. Hormone alone inhibited growth of thymocytes but at certain concentrations stimulated splenocytes. When cultured with prolactin and ConA, the thymocytes of tumor hosts responded with increased proliferation compared to that induced by ConA alone. Glucocorticoid suppressed ConA‐induced lymphocyte proliferation in both normal and tumor‐bearing mice. Prolactin reversed the inhibitory effect of glucocorticoid in normal mice but failed to abrogate inhibition in tumor hosts. Altered responsiveness of lymphocytes of tumor hosts to prolactin was not a function of circulating prolactin, as the serum prolactin level was similar in normal and tumor‐bearing mice. Prolactin, however, could not reverse estradiol‐induced suppression of lymphocyte proliferation. The lactogenic hormone, but not somatogenic hormones, altered the glucocorticoid inhibition of lymphocyte growth.
Lethal deformation of cancer cells in the microcirculation: A potential rate regulator of hematogenous metastasis
Authors: Weiss L. , Nannmark U. , Johansson B. R. , Bagge U.
Published: February 2007

The hypothesis has been advanced that deformation‐induced lethal mechanical trauma, resulting in surface‐membrane rupture, is inflicted on circulating cancer cells trapped in the microcirculation, and that this rapid cell‐killing mechanism is a potentially important rate regulator for hematogenous metastasis. We describe and discuss an in vivo test of this hypothesis. Vital fluorescence microscopy was performed on the microcirculation of cremaster muscle preparations in mice, following retrograde injections into the femoral artery of acridine orange‐stained sarcoma cells. Cancer cells having mean diameters of 16.5 μm in suspension, were deformed from spheres into cylinders having a mean length of 53 μm, in 7‐μm diameter capillaries. Most of these cells were dead several minutes after injection. It was estimated that sphere‐to‐cylinder shape‐transitions of this magnitude required an average increase of 52% in apparent cell surface area. Evidence is presented that most of this apparent increase was achieved by non‐lethal surface “unfolding”, utilizing membrane “excess”. That cancer‐cell deformation of the magnitude observed in vivo is the direct cause of lethal, surface‐membrane rupture was indicated by the observed loss of membrane integrity in cells deformed from spherical to cylindrical shape in vitro, by aspiration into micropipettes of capillary dimensions. The experimental observations are therefore consistent with the hypothesis.
Splicing of the vase exon of neural cell adhesion molecule (NCAM) in human small‐cell lung carcinoma (SCLC)
Authors: van Duijnhoven H. L. P. , Helfrich W. , de Leij L. , Roebroek A. J. M. , van de Ven W. J. M. , Healey K. , Culverwell A. , Rossell R. J. , Kemshead J. T. , Patel K.
Published: February 2007

Expression of the neural cell adhesion molecule (NCAM) on small‐cell lung carcinoma (SCLC) cell lines and tumour tissue has been investigated. Cell lines were found to express highly sialylated NCAM. Neuraminidase treatment revealed the presence of the 140‐ and 120‐kDa isoforms with differential expression of a 95‐kDa protein. Similar data were obtained with SCLC tumour tissues. These results were corroborated by Northern blotting where mRNA of 6.7 and 5.5 kb coding for the 140‐ and 120‐kDa isoforms, respectively, were identified. In a few tumours, a weaker band of 7.4‐kb mRNA coding for the 180‐kDa NCAM was also identified. This result could not be confirmed biochemically due to shortage of material. Finally, a 5‐kb transcript was identified in all SCLC samples examined. The NCAM isoform coded by this mRNA remains unknown. Using the polymerase chain reaction (PCR), we have demonstrated the presence of the VASE mini‐exon in some isoforms of SCLC NCAM. The VASE mini‐exon sequence in human SCLC differs from the published murine sequence by only one base change. This substitution does not result in altered amino‐acid sequence.
Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol
Authors: Turusov V. S. , Trukhanova L. S. , Parfenov Yu. D. , Tomatis L.
Published: February 2007

There is well documented evidence both in humans and in experimental animals that exposure to diethylstilbestrol (DES) during pregnancy results in an increased incidence of tumours in the progeny. The increased cancer risk has been reported to persist in the second generation descendants of DES‐exposed pregnant mice. In the present experiment, female mice of the CBA strain were treated at day 17 of pregnancy with I μg/g body weight of DES. The descendants of DES‐treated mothers, described as F1DES, were mated among each other or with untreated animals. The F1DES females were found to be sterile when mated with either F1DES or untreated males. F1DES males were successfully mated with untreated females. In the female offspring so obtained, but not in the male, a statistically significant increased incidence of tumours was observed, in particular of uterine sarcomas, and also of benign ovarian tumours and of lymphomas.