bluuebunny/crossref_metadata_2025 huggingface dataset:
Human lung cancer—a comparative study of the levels of circulating immune complexes in pulmonary blood draining the tumor area and peripheral venous blood
Authors: Bukh A. , Kimose H.‐H. , Aguado M. T. , Linnet L. , Mösller N. P. H.
Published: February 2007

Our objective was to investigate whether low levels of circulating immune complexes (cICs) in peripheral venous blood of cancer patients could be due to removal of cIC released at the tumor site during passage to the peripheral veins. In 54 patients with primary lung cancer, we therefore compared the cIC levels as detected by 3 different assays in paired samples from the pulmonary vein draining the tumor area and from a peripheral vein. Only 6 of the 54 patients had significantly increased pulmonary vein cIC levels as compared to the corresponding peripheral vein levels. The peripheral vein levels of these 6 patients were all within the normal range, and in none of these patients was the difference between the 2 sites of analysis—although significant—of such a magnitude that the pulmonary vein cIC level appeared higher than the normal range, i.e., “positive” for cIC. Positive cIC levels were only found in 11% of lung cancer patients (irrespective of the site of measurement). Thus, our present data, together with our previous findings indicating no significant difference between peripheral venous blood cIC levels in cancer patients and normal controls, contradict the theory of tumor cells expressing new antigens resulting in the formation of tumor‐associated cICs.
Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance
Authors: Rivoltini Licia , Gambacorti‐Passerini Carlo , Supino Rosanna , Parmiani Giorgio
Published: February 2007

To see whether a tumor cell population may contain cells resistant to lymphokine‐activated killer (LAK) lymphocytes, cells from a LAK‐sensitive melanoma line (Me 665/2) were co‐cultured with LAKs. Three sublines were obtained after 1, 2 or 3 immunoselection cycles. Immunoselected (IS) sublines show reduced proliferation, decreased reactivity to the monoclonal antibody (MAb) R24 and appeared morphologically more differentiated in comparison with the parental Me 665/2 line. A progressively reduced sensitivity to LAKs was observed in IS sublines with a more than 8‐fold reduction in LAK susceptibility. A reduced complement (C)‐mediated lysis was also observed in IS sublines. Since we have previously shown that LAK sensitivity of melanoma cells may be associated with Doxorubicin (Dx) resistance, the sensitivity to Dx was tested in these lines. An augmented sensitivity to Dx was noted in IS sublines as compared with Me 665/2. The differences in LAK susceptibility between the IS sublines and the parental Me 665/2 line remained stable for 2 weeks but declined and disappeared thereafter. These results indicate that (1) a LAK‐sensitive tumor line may contain a subpopulation of cells which are significantly less lysed by LAKs; (2) a correlation between LAK sensitivity and susceptibility to C‐mediated lysis is also present; and (3) increased sensitivity to Dx is evident in the IS sublines.
Acidic cellular environments: Activation of latent tgf‐β and sensitization of cellular responses to tgf‐β and egf
Authors: Jullien P. , Berg T. M. , Lawrence D. A.
Published: February 2007

Transient (about 2 hr) acidification to approx. pH 5.0 of agar‐gelled overlayers containing untransformed NRK‐49F or KiMSV‐transformed NRK‐49F cells in the presence of fetal calf serum or crude 49F‐cell conditioned medium, as sources of latent TGF‐β, elicited EGF‐dependent colony formation of 49F cells and inhibited spontaneous growth of transformed cells. Pure, active TGF‐β (porcine, type 1) had the same effects on these respective cell types, suggesting that the above results were due to activation of latent TGF‐β in the transiently acidic cellular environment. Similar acidifications in the absence of a source of latent TGF‐β enhanced the positive growth response of 49F and AKR‐2B cells to EGF and active TGF‐β and also the negative growth response of KiMSV‐transformed 49F cells to active TGF‐β. These results are compatible with the idea that acidic cellular environments, particularly in tumor tissues, are conducive to activation of latent TGF‐β, perhaps in conjunction with other activating mechanisms, and to an enhanced response to some growth factors. However, the heterogeneity of cell populations within tumoral masses presents an obstacle to a clear understanding of the consequences of such activation.
Stimulatory role of transforming growth factors in multistage skin carcinogenesis: Possible explanation for the tumor‐inducing effect of wounding in initiated nmri mouse skin
Authors: Förstenberger Gerhard , Rogers Michael , Schnapke Ruben , Bauer Georg , Höufler Petra , Marks Friedrich
Published: February 2007

Mechanical wounding provides a convertogenic (“stage 1 tumor‐promoting”) stimulus in initiated NMRI mouse skin, indicating that this stage of carcinogenesis can be entirely controlled by endogenous factors. A search for such factors led to the finding that both platelet‐derived Epstein‐Barrvirus‐inducing factor (EIF), alias human TGFβ1 and porcine TGFβ, exhibited—upon intracutaneous injection—convertogenic efficacy in initiated NMRI‐mouse skin in vivo provided that their injection was combined with a single topical application of the non‐convertogenic tumor promoter 12‐O‐retinolyphorbol‐13‐acetate (RPA). Since TGFβ inhibits epidermal cell proliferation, the RPA treatment is thought to provide a mitogenic stimulus required for conversion. The RPA treatment can be replaced by intracutaneous injection of transforming growth factor α (TGFα). These results indicate that the stage of conversion consists of two components, one of which is related to mitogenesis (RPA or TGFα), the other to a still unknown activity exhibited by TGFβ‐like factors. Thus, endogeneous factors with the quality of “wound hormones” may be involved in multistage skin carcinogenesis. This finding could explain the convertogenic effect of skin wounding.
A carcinoembryonic antigen‐directed immunotoxin built by linking a monoclonal antibody to a hemolytic toxin
Authors: Avila A. D. , Mateo Acosta C. De , Lage A.
Published: February 2007

Hybrid molecules prepared by linking toxins to monoclonal antibodies (MAbs) are cytotoxic to cells bearing the target antigen. The toxin most widely used has been the plant toxin ricin as the toxic component, which inhibits protein synthesis at the ribosome level. Immunotoxins based on membraneactive, hemolytic toxins can be a useful alternative when directed towards antigens which do not mediate internalization, as is the case for most carcinoma antigens. We present an alternative for toxic components using a hemolytic toxin acting at the membrane level, due to its phospholipase activity. The hemolytic toxin (HT), isolated from the sea anemone Stoichactis helianthus, has been conjugated to a MAb directed against carcinoembryonic antigen (CEA), by means of an artificial disulphide bridge. The hybrid α CEA‐HT exhibits no hemolytic activity unless it is reduced. It is toxic for cells (MDA‐MB‐134) expressing CEA and not toxic for cells (MDA‐MB‐231) not bearing CEA. An excess of free antibody reverses toxicity.
Cytogenetics of undifferentiated nasopharyngeal carcinoma xenografts from southern chinese
Authors: Huang D. P. , Ho J. H. C. , Chan W. K. , Lau W. H. , Lui M.
Published: February 2007

Three undifferentiated nasopharyngeal carcinoma (NPC) tumour lines were successfully established from fresh biopsy material injected s.c. into athymic mice and passaged for many generations. These xenografts were found to be free of infiltrating lymphoid cells and remained undifferentiated up to passage 30. They were designated NPC/HK2117 (Xeno‐1), NPC/HK1915 (Xeno‐2) and NPC/HK1530 (Xeno‐3), respectively. Passage 16 from Xeno‐1, passage 1 from Xeno‐2 and passage 14 from Xeno‐3 were studied cytogenetically using G‐banding with the trypsin‐Giemsa method. Two xenografts were hyperdiploid with chromosome modal numbers ranging from 49 to 76, and one was hypodiploid with modal numbers ranging from 28 to 38. Five marker chromosomes have been identified with involvement of chromosomes 1, 3, 11, 12 and 17. Marker chromosomes derived from chromosomes 12q, 1q and 3q were consistent in one of the 2 xenografts successfully G‐banded, and chromosomes 12, 11 and 17 were consistent in another. Three out of the 6 markers involve 12q13 qter. An abnormal chromosome 3 with most of the p arm deleted was also observed.
A functional and phenotypic comparison of murine natural killer (NK) cells and lymphokine‐activated killer (LAK) cells
Authors: Hoskin D. W. , Stankova J. , Anderson S. K. , Roder J. C.
Published: February 2007

Lymphokine‐activated killer (LAK) cells have been defined as interleukin 2 (lL‐2)‐activated cytolytic effector cells exhibiting non‐MHC restricted killing against a wide range of NK‐sensitive and NK‐resistant tumor cells. There has been considerable debate as to whether LAK cells are derived from NK cells or from a unique precursor population. In the present study, we compare LAK cells derived from T‐cell‐depleted nylon‐wool‐non‐adherent spleen cells with endogenous NK cells and NK cells activated with the interferon inducer polyl.C., in terms of their phenotype and functional characteristics. The predominant splenic LAK precursor in the mouse was found to be a nylon‐wool‐non‐adherent, thyl‐, MICG,‐,Jlld.2, asialo GM1+ cell. This phenotype is shared by endogenous NK cells. A significant number of activated NK cells express macromolecular insoluble cold globulin (MICG) in addition to asialo GM1. Neither endogenous nor activated NK cells express a heat‐stable antigen found on bone‐marrow cells, immature T cells, and most B cells and defined by monoclonal antibody (MAb)Jlld.2. However, Jlld.2 is expressed on some LAK precursor and effector cells. The asialo GM1 marker is common to all LAK effector cells, while many are also thyl+, and or MICG+. LAK effector cells are therefore a heterogeneous population sharing some phenotypic characteristics in common with NK cells. In addition, there is a positive correlation between LAK and NK activity in “high NK” and “low NK” mouse strains, suggesting that NK cells and LAK cells share a common lineage. Monoclonal antibodies to the alpha and beta chains of LFA‐1 inhibit LAK and activated NK function, while endogenous NK and CTL killing is affected only by anti‐alpha chain antibodies. LAK cells, like MHC‐restricted and non‐restricted CTL clones, express mRNA transcripts of the C11 serine protease gene. We conclude that LAK cells share several features in common with cells of the NK lineage and may therefore represent NK cells in a unique state of activation. LAK cells appear to employ cytolytic machinery common to other lytic cell types.
A prospective study of the independent effects of parity and age at first birth on breast cancer incidence in England and Wales
Authors: Leon D. A.
Published: February 2007

The independent effects of parity and age at first birth on breast cancer incidence are investigated in a 1% sample of women aged 16 to 59 from the 1971 Census of England and Wales. Over the period 1971–81, 1,003 breast cancer cases occurred in the cohort of 113,263 women who were either married, widowed or divorced at the time of Census. Age at first birth was positively related to breast cancer risk, women giving birth to their first child after 35 years being at greater risk than nulliparous women. This effect remained, after adjustment for number of live‐born children. Breast cancer risk showed a statistically significant decline with increasing parity even after adjustment for age at first birth. These results are consistent with other published evidence which suggests that other births subsequent to the first have an independent effect on breast cancer risk.
Binding of epidermal growth factor and insulin‐like growth‐factor I in renal carcinoma and adjacent normal kidney tissue
Authors: Pekonen Fredrika , Partanen Seppo , Rutanen Eeva‐Marja
Published: February 2007

The binding of epidermal growth factor (EGF) and insulinlike growth factor I (IGF‐1) to cell membranes was determined in 14 renal cancers and in 13 normal kidney tissues adjacent to the tumors. The soluble 34K 1GF binding protein (34K IGF‐BP) content and the phosphotyrosyl‐protein phosphatase activity in renal cancer tissue and adjacent normal tissue were also determined. The specific EGF receptor binding in renal cancers was 12.7 ± 2.5% (mean ± SEM) as compared to 2.6 ± 0.2% (mean ± SEM) in normal tissues (p < 0.01). Phosphotyrosyl‐protein phosphatase activity in renal cancer tissue was less than half of that observed in normal renal tissue (p < 0.01). The highest IGF‐1 binding was observed in 5 renal cancers although no consistent differences between IGF‐1 binding to tumor and normal tissues were observed. Both EGF and IGF binding to kidney tissue were higher than binding to gastro‐intestinal tissue irrespective of whether normal or malignant tissues were compared. All normal kidney tissues and 7 of 8 kidney tumors contained measurable amounts of 34K IGF‐BP as determined by RIA and the cross‐linking technique. In 2 tumor tissue samples the 34K IGF‐BP content was increased 8‐ and 15‐fold over that seen in adjacent normal kidney tissue, whereas in the 6 other renal cancers the 34K IGF‐BP was similar to that observed in normal kidney tissue.
High frequency of Ki‐ras codon 12 mutations in pancreatic adenocarcinomas
Authors: Grünewald Kurt , Lyons John , Fröhlich Anja , Feichtinger Hans , Weger Richard A. , Schwab Gerhard , Janssen Johannes W. G. , Bartram Claus R.
Published: February 2007

The frequency of Ki‐ras gene mutations was studied in 100 paraffin‐embedded sections obtained from 63 pancreatic adenocarcinomas by in vitro amplification of target sequences via polymerase chain reaction (PCR) and selective oligonucleotide hybridization. Forty‐seven (75%) of the tumors contained a Ki‐ras mutation at codon 12. No predominant amino acid substitution or nucleotide transition at this codon was observed. Two carcinomas exhibited 2 distinct Ki‐ras mutations. No particular correlation could be established between the incidence of Ki‐ras mutation and clinical parameters (sex, age, survival), tumor grade or tumor stage.
Age‐ and sex‐specific cumulative rate and risk of ATLL for HTLV‐I carriers
Authors: Kondo Toshifumi , Kono Hidehisa , Miyamoto Naoaki , Yoshida Ryouichi , Toki Hironobu , Matsumoto Isao , Hara Masamichi , Inoue Hiroo , Inatsuki Akira , Funatsu Takashi , Yamano Norio , Bando Fumihiro , Iwao Eiichi , Miyoshi Isao , Hinuma Yorio , Hanaoka Masao
Published: February 2007

We have surveyed the incidence of adult T‐cell leukemia/lymphoma (ATLL) in an endemic area of 290,464 inhabitants for 7 years. We now revise our previous results on the basis of additional findings and estimate the age‐ and sex‐specific cumulative rate for HTLV‐I carriers, the adoption of which is recommended by current cancer epidemiology as a new age‐standardized incidence rate. An unequivocal age‐dependent increase in seroprevalence was observed for both sexes with a characteristic predominance in females. The age‐dependent seroconversion in females may be partly explained by additional infection from infected husbands to their wives but the reason for men remains obscure. The mean annual number of incident cases of ATLL was 11.4, giving 3.9 ATLL patients annually per 105 inhabitants, 6.1 per 105 inhabitants aged over 30, and 85.0 per 105 seropositives aged over 30. Crude annual incidence rate of ATLL among 105 male seropositives aged over 30 was 145.3 and that for females was 55.2 and 95% confidence intervals of ATLL incidence rates were 34.8 to 255.7 for males and 6.4 to 104.1 for females, respectively. Although the sex ratio of 80 ATLL patients was 1.35, males are more prone to the disease (46 male patients among 4,522 male seropositives aged over 30 vs. 34 female patients among 8,801 female seropositives aged over 30; p < 0.001) for unknown reason(s). Morbidity in male seropositives aged over 30 is 2.6 times as high as that of females. Decennial incidence rates in males in their fifties and sixties were significantly higher than those in females. The remarkable male preponderance in oncogenicity of HTLV‐I may be due to the fact that men are more prone to the disease and the number of female carriers in the denominator used to calculate the incidence rate is larger than that of males. The whole life span (0–79) cumulative risk for males was 6.9% and significantly higher than that of females (2.95%).
Characterization of a novel mouse reticular cell sarcoma M5076 subline resistant to cisplatin
Authors: Ferrari A. , Damia G. , Erba E. , Rossi C. , Mandelli R. , D'incalci M.
Published: February 2007

A novel murine tumor resistant to cis‐diamminedichloroplatinum (cisplatin, DDP) was obtained (M5/DDP) after 22 passages in which mice bearing the ovarian reticular cell sarcoma M5076 (M5) were treated with DDP. Although DDP conserved some inhibitory activity on growth of M5/DDP, it was much less effective than on M5. Treatment with DDP did not prolong the survival time of mice with M5/DDP, whereas it markedly prolonged survival of M5‐bearing mice. MS and M5/DDP tumors shared many biological and biochemical features. They were similar histologically, they metastasized reproducibly to the liver and were poorly immunogenic. Their growth rates were comparable; their DNA index, percentage of cells in S phase and intra‐cellular glutathione content were also similar. In both tumors, DDP caused an accumulation of cells in S late‐G2‐M within 24 hr after drug treatment. However, this was efficiently reversed in M5/DDP, whereas it worsened and persisted longer in M5. Cross‐resistance was observed between DDP and its analogues carboplatin and iproplatin, but tetraplatin retained marginal activity on M5/DDP tumor. Several alkylating agents tested [L‐phenylalanine mustard (L‐PAM); cyclophosphamide (CTX); chlorambucil (CLB); 1,3‐bis(2‐chloroethyl)‐I‐nitrosourea (BCNU) and dacarbazine (DTIC)] were not totally cross‐resistant to DDP, but showed greater activity on M5 than on M5/DDP. Other non‐alkylating anti‐neoplastic drugs showed a similar degree of activity on M5 and M5/DDP. 5‐Aza‐2′‐deoxycytidine (Aza‐d‐Cyd) was very effective on both tumors, etoposide (VP‐16) and cytosine arabinoside (Ara‐C) had no activity and Adriamycin (ADR) was weakly effective.
Distinct chromosomal abnormalities in murine leukemia virus‐induced T‐ and B‐cell lymphomas
Authors: Vasmel W. L. E. , Matthews E. A. , Gillis C. P. M. , Nieland J. , Borst E. A. , Leupers C. J. M. , Melief C. J. M. , Slater R. M.
Published: February 2007

We performed a cytogenetic study on 16 murine mature B‐cell lymphomas and 10 T‐cell lymphomas, using G‐banding techniques. All tumors, with the exception of 3 spontaneous B‐cell tumors, were induced by various slowly transforming murine leukemia virises (MuLV). Metaphases were obtained from primary (10 B‐cell tumors) and first or second transplant generation lymphomas (6 B‐cell and 10 T‐cell tumors), all of which were well characterized with respect to phenotypic, histologic and genotypic features. In the T‐cell tumors we found relatively simple karyotypic abnormalities, including various numerical aberrations, such as trisomy 15, in line with many earlier reports. However, the majority of B‐cell tumors showed a great variety of both structural and numerical chromosomal anomalies. Three B‐cell lymphomas had an apparently normal karyotype. No single cytogenetic abnormality occurred commonly in the B‐cell lymphomas, but some structural abnormalities were found in more than one stemline, in particular, ins (11) (A1; A2) in 3 tumors, and deletions involving the D‐region of chromosome 14 in 3 other lymphomas. These cytogenetic results clearly indicate that the pathogenic mechanisms involved in MuLV‐induced (long latency) B‐cell lymphomagenesis and (short latency) T‐cell lymphomagenesis differ considerably.
Retrovirally induced murine B‐cell tumors rarely show proviral integration in sites common in T‐cell tumors
Authors: Matthews E. A. , Vasmel W. L. E. , Schoenmakers H. J. , Melief C. J. M.
Published: February 2007

The molecular etiology of retrovirally induced T‐cell tumors has been shown in many cases to involve proviral integration near a cellular oncogene, c‐myc, N‐myc, Pim‐1 and pvt‐1 being frequent targets for insertional activation. Murine B‐cell tumors induced by infection with murine leukemia virus have been studied for rearrangements in these and other loci. In contrast to the T‐cell lymphomas, tumors of the B‐cell lineage, either early B‐cell tumors induced in nude mice or late B‐cell tumors in immunocompetent mice, did not show disruption of N‐myc or Pim‐1 in any of the tumors studied, although those lymphomas had acquired many new proviruses. The loci c‐abl, bcl‐2, fis‐1, c‐erbB, c‐myb, and neu were likewise not involved. Rearrangement of c‐myc was seen in 1 out of 71 and rearrangement of the pvt‐1 locus in 4 out of 73 (5%) of the B‐cell tumors. Thus it appears that mechanistic differences exist in the development of T‐cell tumors and B‐cell tumors caused by the same etiological agent.
Quantitative determination of water‐ and lipid‐soluble antioxidants in neoplastic and non‐neoplastic human breast tissue
Authors: Langemann H. , Torhorst J. , Kabiersch A. , Krenger W. , Honegger C. G.
Published: February 2007

Ascorbic acid, cysteine, glutathione and uric acid were determined by reverse‐phase high‐pressure liquid chromatography (HPLC) in 46 breast tissue samples [neoplastic (C) and non‐neoplastic (N) from the same patient]. Cholesterol, α‐tocopherol and γ‐tocopherol were quantified in 64 similar samples by extraction into heptane followed by direct‐phase HPLC. DNA was measured in all samples and the percentages of epithelium, fat and connective tissue were estimated in sections adjacent to the sample. Results confirm previous findings that ascorbic acid and glutathione, expressed as μmol/g DNA, were greatly increased in the epithelium of neoplastic tissue. Similar increases in cysteine could be accounted for by the presence of inflammatory cells. Although values of α‐ and γ‐tocopherol correlated with the percentage of fat in both types of tissue, these compounds were also present in the epithelium. Because of the varying amounts of fat in the samples, no significant difference could be found between N and C values. Cholesterol correlated with fat in N and epithelium in C. Consideration of 10 cases with equal amounts of fat in C and N tissue suggests that cholesterol is reduced in C in the epithelial cells.
Growth rate, kinetics of tumor cell proliferation and long‐term outcome in human breast cancer
Authors: Tubiana Maurice , Pejovic Marie Héléne , Koscielny Serge , Chavaudra Nicole , Malaise Edmond
Published: February 2007

Thymidine labelling index (LI) was prospectively assayedin vitroin a series of 128 consecutive patients with breast cancer. The follow‐up was longer than 15 years for all patients. The distribution of LI was log normal and patients were subdivided into 3 groups (patients with LI = m ± σ, lower than m — σ and greater than m + σ where m is the geometrical mean). The incidence of relapse and death remained significantly lower in the group with a low LI than in the 2 other groups, whereas the difference between the 2 other groups faded away when follow‐up exceeded 10 years. Multivariate analyses show that LI is one of the two most important independent prognostic indicators for relapse or death, the other being histological grading. Data concerning 2,648 patients treated at our Institute, prior to the introduction of chemotherapy into treatment protocols, have been used to investigate the influence of tumor growth rate on the probability of distant dissemination. A model of the natural history was used, in order to generate metastasis appearance curves, in 3 subgroups of patients, according to the value of the tumor doubling time (TDT). Our results show that after a follow‐up exceeding 8 years, there is no longer any difference between the subgroups of patients with rapid or intermediate growth rate, whereas after 25 years large and highly significant differences in relapse and survival between the slow‐growing tumors and the other two subgroups still remain. These two sets of data concur to show that tumor growth rate or proliferation rate correlates with the probability of metastatic dissemination.
Nuclear DNA, serum sialic acid and measured depth in malignant melanoma for predicting disease recurrence and survival
Authors: Silver Hulbert K. B. , Karim Karim A. , Riche Jean Le , Jong Gary De , Spinelli John , Worth Ann , McLean David I. , Gallagher Richard
Published: February 2007

In a previous multivariate analysis of 151 malignant melanoma patients we identified measured depth of primary lesion (Breslow) and serum N‐acetyl‐neuraminic acid (NANA) concentration as significant independent predictors of recurrence. Our present study examines the contribution of flow cytometric DNA analysis to prediction of recurrence and survival. Fixed, paraffin‐embedded specimens of primary lesions were evaluated from 63 of the previously studied patients. These were prepared for DNA analysis. Of the 28 primaries identified as aneuploid 17 later recurred, while this was true for only 9 of the 35 diploid tumors. On multivariate analysis measured depth was again the most significant predictor of recurrence (p< 0.001). Additional independent predictors were DNA ploidy (p= 0.02) and NANA (p= 0.05). For survival the independent predictors were measured depth (p= 0.003) and NANA (p= 0.05). Measured depth, DNA ploidy and NANA can be used to construct a model predicting the recurrence risk for stage‐1 melanoma.
Early diagnosis of bilateral retinoblastoma reduces death and blindness
Authors: Derkinderen D. J. , Koten J. W. , Van Romunde L. K. J. , Nagelkerke N. J. D. , Tan K. E. W. P. , Beemer F. A. , Den Otter W.
Published: February 2007

The influence of early diagnosis on sight and survival was studied in 130 patients with bilateral retinoblastoma. Nineteen patients died of this condition. Statistical analysis predicted that 12 of these 19 early deaths could have been prevented if doctors' delay had been less than I week. Consequently, a reduction of 65% in mortality is possible. Similarly, statistical analysis also predicted that the number of patients with resulting blindness could be reduced by 40%. Central registration and monitoring of retinoblastoma families would greatly improve early diagnosis.
Cytogenetic study on eleven cutaneous neoplasms and two pre‐tumoral lesions from xeroderma pigmentosum patients
Authors: Aledo Rosa , Dutrillaux Bernard , Lombard Martine , Aurias Alain
Published: February 2007

Eleven independent tumors (5 basal‐cell carcinomas, 5 squamous‐cell carcinomas and 1 malignant melanoma), 2 pre‐tumoral lesions and one common nevus, developing in the skin of 10 unrelated XP patients were cytogenetically analyzed. No specific chromosomal changes were observed. Two features were relevant, however: emergence of several independent clones and over‐involvement of telomeric and cen‐tromeric regions in the formation of chromosomal rearrangements, jumping translocations were observed in 2 squamous‐cell carcinomas involving telomeric and centromeric regions.
Interleukin‐1β induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti‐tumor effects of tumor necrosis factor α or β
Authors: Belardelli F. , Proietti E. , Ciolli V. , Sestili P. , Carpinelli G. , Di Vito M. , Ferretti A. , Woodrow D. , Boraschi D. , Podo F.
Published: February 2007

Peri‐tumoral injection of recombinant human interleukin‐I ß in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3CI‐8) with IL‐Iß barely inhibited cell multiplication. IL‐Iß, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL‐Iß of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL‐I injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF‐α or ß. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within I hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri‐tumoral injection of IL‐Iß or TNF‐ß. After 6 hr, both cytokines induced a 3‐fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophospho‐rylethanolamine, an accumulation of sn‐glycerol 3‐phosphate and a more than 10‐fold increase in the choline/phosphoryl‐choline ratio. These results are similar to those reported for TNF‐α, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 3.1.4.2) and partial inhibition of choline kinase (EC 2.7.1.32). IL‐Iß and TNF‐ß (like TNF‐α) also induced alkaline shifts (0.10‐0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL‐Iß or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.
Enhanced tumor growth and metastatic spread of an mh 134 variant lacking a part of the mm antigen: A possible role of antibody‐dependent cellular cytotoxicity in control of tumor growth and metastases
Authors: Hara Hideki , Kawase Ichiro , Komuta Kiyoshi , Masuno Tomiya , Kishimoto Susumu
Published: February 2007

The role of antibody‐dependent cellular cytotoxicity (ADCC) in host defense against tumor growth and metastasis was investigated with MH134, an MM antigen‐positive murine hepatoma, and MH134‐M, a variant with enhanced tumori‐genesis and metastasis, in syngeneic C3H/HeN mice. When inoculated subcutaneously into C3H/HeN mice, MH134‐M tumors grew more rapidly than did MH134 tumors and consistently metastasized to the draining lymph nodes, whereas MH134 tumors did not. Also, MH134‐M exhibited a significantly greater lung colonization potential than did MH134, when inoculated intravenously into C3H/HeN mice. In BALB/c nu/nu mice, however, solid MH134 tumors grew and metastasized to the same extent as MH134‐M, indicating that there is no significant intrinsic difference between these two tumor lines in proliferative or metastatic capacity. Enzyme‐linked immunosorbent assay (ELISA) and immunoblotting, performed after SDS‐PAGE analysis of cellular extracts with a monoclonal antibody (MAb) that recognizes a part of the MM antigen, revealed that the cells of MH134‐M lack at least a part of the MM antigen. Sera of C3H/HeN mice bearing solid MH134 tumors were found to contain anti‐MM‐antigen antibodies, when tested by immunoblotting of SDS‐PAGE‐developed materials. Cytotoxicity testing in which thioglycol‐late‐induced peritoneal macrophages were used as effector cells revealed that antibodies present in sera strongly induced ADCC to MH134 but not to MH134‐M. On the other hand, sera of MH134‐M tumor‐bearing C3H/HeN mice neither contained anti‐MM‐antigen antibodies nor induced ADCC to MH134 or MH134‐M tumor cells. Intravenous injection of car‐rageenan into C3H/HeN mice bearing solid MH134 tumors significantly enhanced tumor growth, whereas the growth of subcutaneously injected MH134‐M tumors was not influenced by this treatment. These results suggest that the enhanced tumorigenesis and metastasis of the MH134‐M line in C3H/ HeN mice are based, at least in part, on significant loss of the MM antigen and the resultant inability to induce ADCC‐triggering antibody production during tumor growth.
Identification by C‐banding of two human prostate tumour cell lines, 1013L and DU 145
Authors: Hartley‐Asp Beryl , Billström Anita , Kruse Elisabeth
Published: February 2007

Two human prostate carcinoma cell lines are easily distinguished by C‐banding. DU 145 has one metacentric chromosome with a large centromeric band, I metacentric and 2 acrocentric chromosomes with interstitial C‐bands. The Y chromosome was present in 48% and 42% of the cells at passages 83 and 106, respectively, whereas in I0I3L only one metacentric chromosome contained distinct extra C bands—one at the centromere and one interstitially. The Y chromosome was present in 72% of the cells at passage 15 and in 20% at passage 22, but by passage 44 it had disappeared. Karyotype analysis using G‐banding revealed that DU 145 had retained several of its original markers, and demonstrated multiple marker chromosomes in 1013L.
Abnormal DNA content in liver‐cell dysplasia: A flow cytometric study
Authors: Roncalli M. , Borzio M. , Brando B. , Colloredo G. , Servida E.
Published: February 2007

To clarify the true nature of liver‐cell dysplasia (LCD), a flow cytometric study has been performed. The DNA content of hepatocytes from 26 cases of cirrhosis with diffuse areas of LCD was investigated and compared to that of hepatocytes from 21 control patients with non‐neoplastic and neoplastic liver conditions. Flow cytometric analysis was performed on propidium‐stained nuclei from archival paraffin‐embedded material. Analysis was directed to assessment of diploid as well as non‐diploid peaks by calculation of DNA index (Dl), using normal hepatocytes present in each sample as individual and specific references. Since only samples containing at least 10,000 nuclei were considered suitable for analysis, 4 of the 26 LCD cases were discarded. Eight of 22 LCD cases had an abnormal DNA content compared with 0/11 non‐neoplastic cases (p < 0.05) and 8/10 hepatocellular carcinomas (p < 0.05). Nonneoplastic control cases displayed uniformly diploid stemlines whereas hepatocellular carcinomas had in 8/10 cases bimodal or trimodal populations. Thus, LCD is a heterogeneous lesion in terms of ploidy, and the abnormal DNA content observed in some cases supports its pre‐neoplastic nature.
Serologic mapping and biochemical characterization of the carcinoembryonic antigen epitopes using fourteen distinct monoclonal antibodies
Authors: Kuroki Masahide , Greiner John W. , Simpson Jean F. , Primus F. James , Guadagni Fiorella , Schlom Jeffrey
Published: February 2007

A series of 14 monoclonal anti‐carcinoembryonic antigen (CEA, Mr 180,000) antibodies (MAbs) that show a strong degree of selective reactivity for human colon carcinomas versus normal adult tissues were used to construct a serological map of the CEA molecule. The MAbs were generated using extracts of colon carcinomas as immunogen and are thus given a COL designation. None of the 14 COL‐MAbs tested were reactive with purified non‐specific cross‐reacting antigen (NCA, Mr 55,000) from normal lung, although some showed reactivity to human granulocytes. All the COL‐MAbs tested were reactive with normal fecal antigen‐2 (NFA‐2, Mr170,000); however, many of the COL‐MAbs demonstrated a higher affinity constant to CEA than to NFA‐2. Cross‐competition radioimmunoassays classified the 14 COL‐MAbs into 5 groups. The chemical nature of the COL‐binding domains was tested using chemically or enzymatically treated CEA; all reacted with periodate‐treated CEA and deglycosy‐lated CEA, indicating that the COL‐reactive epitopes appear to be of a proteinaceous nature. Heat treatment, reduction, alkylation, pepsin digestion or pronase treatment of CEA, however, gave differential results with respect to COL binding. Antibody titration experiments were carried out to define differential reactivities to colorectal carcinoma versus NCA‐containing granulocyte extracts; these results were compared with results obtained using several anti‐CEA MAbs that have been used in clinical trials. Granulocyte binding and biochemical studies showed that the COL MAbs may distinguish as many as 7 to 10 CEA epitopes.
Human tumor‐infiltrating lymphocyte (TIL) cytotoxicity facilitated by anti‐T‐cell receptor antibody
Authors: Schoof Deric D. , Jung Sung‐Eun , Eberlein Timothy J.
Published: February 2007

Long‐term growth of tumor‐infiltrating lymphocytes (TIL) in high concentrations of rlL‐2 is required for generation of therapeutic numbers of cells for adoptive immunotherapy of human cancer. Under these conditions rlL‐2 promotes both anti‐tumor cytotoxicity and lymphocyte growth from tumors of several histological types. In a series of 16 consecutive tumors, studies of TIL‐mediated cytotoxicity against different tumor targets were characterized by an initial strong tumor‐non‐specific cytotoxicity. With time, TIL bulk cultures became non‐cytotoxic against all targets (median time = 38 days). Non‐cytotoxic TIL bulk populations were capable of mediating strong cytotoxic responses if pre‐treated with anti‐T‐cell antigen receptor antibody (TcR) before addition to targets. TIL populations were not, however, uniformly susceptible to anti‐TcR‐mediated cytotoxicity. Anti‐TcR‐mediated cytotoxicity was confined to CD8+ bulk populations (defined as populations with a CD4/CD8 ratio 2), (p < 0.01). Both CD4 and CD8 populations expressed TcR antigen reactive with anti‐TcR antibody. These results indicate that, despite poor in vitro anti‐tumor cytotoxicity in short‐term assays, CD8+ TIL are fully competent cytotoxic effector cells when subjected to strong activation signals via the TcR complex. In addition, these results imply that adoptively transferred CD4+ populations of TIL have in vivo biologic functions quite distinct from those of CD8+ populations and, further, that disparate clinical outcomes could reasonably be expected from the adoptive transfer of either population alone.
Cancer incidence among spouses of patients with colorectal cancer
Authors: Mellemgaard Anders , Jensen Ole Møller , Lynge Elsebeth
Published: February 2007

The risk of colorectal cancer was examined among spouses of approximately 10,000 colorectal cancer patients. A total of 8,095 spouses were identified, and cancer cases in this cohort were sought in the Danish Cancer Registry. No excess risk was found for colorectal cancer as such. The data were also anal/zed by subsite of the large bowel for the index cases and for the spouses, respectively. The estimated relative risks were in general close to unity, the only exception being the risk of right‐sided colon cancer among husbands of index cases with left‐sided colon cancer, RR = 2.17 (p < 0.05). The absence of excess risk was noted regardless of the duration of marriage. The risk of other cancers with a presumed etiology similar to that of colorectal cancer (cancer of the uterine corpus, breast, prostate and biliary tract) was also close to expected values.
in situ oestrone synthesis in normal breast and breast tumour tissues: Effect of treatment with 4‐hydroxyandrostenedione
Authors: Reed M. J. , Owen A. M. , Lai L. C. , Coldham N. G. , Ghilchik M. W. , Shaikh N. A. , James V. H. T.
Published: February 2007

An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H‐Androstenedione and 14C‐oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H‐androstenedione, 3H‐oestrone derived from 3H‐androstenedione and 14C‐oestrone were isolated and measured. DNA polymerase α activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4‐hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H‐oestrone from 3H‐androstenedione accounted for the major part (84.3 ± 9.0%) of the 3H‐oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4‐hydroxyandrostenedione did not significantly alter the uptake of 3H‐androstenedione or 14C‐oestrone into breast tissues, in situ formation of 3H‐oestrone was only detected in one tumour sample after treatment. DNA polymerase α activity decreased in 4/6 tumours after treatment with 4‐hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H‐oestrone formed in situ and DNA polymerase α activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.
Polymorphism of the c‐Ha‐ras‐1 proto‐oncogene in sporadic and familial breast cancer
Authors: Barkardóttir Rósa B. , Jóhannsson Óskarth , Arason Adalgeir , Gudnason Vilmundur , Egilsson Valgardur
Published: February 2007

Two studies on breast cancer patients are described. Our aim was to examine whether the combined frequency of rare c‐Ha‐ras‐l alleles in cancer patients was raised. Firstly, the c‐Ha‐ras‐l locus in 56 breast cancer patients and 48 controls was examined for restriction fragment length polymorphism (RFLP) by Southern blot analysis of leukocyte DNA. Four predominant allelic fragments were found in both groups together with a variety of rare alleles. The 2 groups did not differ significantly in overall distribution of c‐Ha‐ras‐l alleles. Rare alleles combined were about as frequent in cases (7.1 %) as in controls (6.3%). Secondly, 53 members of 3 families having a high incidence of breast cancer were c‐Ha‐ras‐l genotyped. None of 10 affected members was found to carry a rare c‐Ha‐ras‐l allele. The only c‐Ha‐ras‐l allele common to 11 affected members was a 6.8‐kb allele which is found in 72% of the controls. Furthermore, this allele was found with equal frequency in affected and non‐affected family members.
Tumor blood flow: The principal modulator of oxidative and glycolytic metabolism, and of the metabolic micromilieu of human tumor xenografts in vivo
Authors: Kallinowski F. , Schlenger K. H. , Kloes M. , Stohrer M. , Vaupel P.
Published: February 2007

We have investigated therapeutically relevant pathophysiological parameters of human breast and lung cancer xenografts in nude rats. All lung cancers and one breast cancer exhibited rapid growth and high blood flow values paralleled by high metabolic rates. The tissue of these tumors was well oxygenated up to very advanced growth stages. Xenografts from other breast cancer cell lines grew much more slowly, were poorly perfused, and exhibited low metabolic rates. Here, tumor hypoxia and tissue acidosis were evident. These results indicate that significant differences in the metabolic micromilieu can be detected in human tumors; these are due to varying perfusion rates and may be partly responsible for failure to obtain tumor control in individual patients.
Fibronectin/laminin and their receptors in aberrant growth control in FR3T3 cells transformed by ha‐ras oncogene and epidermal growth factor gene
Authors: Chakrabarty Subhas , Jan Yih , Levine Alan , McClenic Brian , Varani James
Published: February 2007

FR3T3 cells transfected with either the Ha‐ras oncogene or the epidermal‐growth‐factor (EGF) gene demonstrate the transformed phenotype as indicated by in vitro and in vivo criteria. We have examined non‐transformed FR3T3 cells as well as Ha‐ras‐oncogene‐transformed and EGF‐gene‐trans‐formed cells for expression of cell surface fibronectin and cell surface laminin. Fibronectin was absent from the surface of the Ha‐ras‐oncogene‐transformed cells but present on both the EGF‐gene‐transformed cells and the non‐transformed FR3T3 cells. Laminin was present on the cell surface in all 3 lines. The lack of surface fibronectin on the Ha‐ras‐oncogene‐transformed cells was associated with reduced fibronectin production as indicated by immunoblotting of whole cell extracts and by ELISA. Concomitantly, there was a significant reduction of fibronectin binding by the Ha‐ras‐oncogene‐transformed cells as compared to their EGF‐gene‐transformed and non‐transformed counterparts. The Ha‐ras‐oncogene‐transformed cells demonstrated reduced cell‐substrate adhesiveness relative to the other two cell lines, as indicated by rates of attachment and spreading on plastic culture dishes in the presence of bovine serum albumin. They also demonstrated reduced adhesiveness in response to fibronectin but not laminin. Taken together, our results suggest that aberrant expression of fibronectin/fibronectin receptors is associated with Ha‐ras‐oncogene‐induced transformation. In contrast, transformation by the EGF gene does not appear to involve aberrant expression of fibronectin/ fibronectin receptors.
Relationship between tumorigenicity and the dosage of lymphoma‐ vs. Normal‐parent‐derived chromosome 15 in somatic cell hybrids between lymphoma cells with rearranged pvt‐1 gene and normal cells
Authors: Uno Masatsune , Wirschubsky Zwi , Wiener Francis , Klein George
Published: February 2007

Somatic cell hybrids were generated between YACUT, a doubly drug‐resistant subline of YAC‐I (a Moloney‐virus‐induced T‐cell lymphoma of strain A/Sn origin with 2 pro viral insertions near the pvt‐1 locus) and normal diploid fibroblasts of CBAT6T6 origin. Three independent fusions were performed. Three uncloned hybrid cultures and 9 independently‐derived clones were tested for tumorigenicity by the inoculation of graded cell numbers into syngeneic hosts. One of 3 uncloned hybrid cultures and 3 of 9 clones were weakly tumorigenic (take incidence 0%), and 1 of 3 uncloned hybrid cultures and 6 clones were highly tumorigenic (take incidence >80%). One weakly tumorigenic hybrid and 3 weakly tumorigenic clones carried 3 copies of the tumor‐derived chromosome 15 and 2 copies of the normal fibroblast‐derived t(l4;l5) chromosomes. In contrast, 2 highly malignant hybrid clones lost one copy of the normal‐fibroblast‐derived t(14;15), but contained increased numbers (3.44‐4.44) of the tumor‐derived chromosome 15. Four tumorigenic segregants selected from the weakly tumorigenic fibroblast hybrids by in vivo inoculation showed the same cytogenetic change as the highly tumorigenic hybrid clones, in that the ratio of the normal:tumor‐derived chromosomes 15 changed from 1.18‐1.55 to 4.11‐5.71. Tumorigenicity was thus associated with a modified balance between the tumor vs. the normal‐parent‐derived 15‐chromosomes. Instead of the usual 3:2 ratio, the tumor‐derived 15‐chromosomes increased disproportionately, whereas the relative number of the normal‐parent‐derived 15‐chromosome decreased, as a rule. These results suggest that amplification of the lymphoma‐derived chromosome 15 favors tumorigenicity, but that this effect is counteracted by some influence emanating from the normal‐parent‐derived homologous chromosome.
Efficacy of two‐route chemotherapy using cis‐diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, in combination with angiotensin II for rat liver tumor
Authors: Hasuda Keitaro , Kobayashi Hiroaki , Aoki Ken , Taniguchi Shun'ichiro , Baba Tsuneo
Published: February 2007

To improve the therapeutic effects of conventional TRC using i.a. CDDP plus simultaneous i.v. STS in a rat liver tumor, we made use of the AT‐II‐induced hypertension method, in combination with TRC. The decrease in tumor area (‐15%), measured 8 days after the TRC using CDDP 12 mg/ kg i.a. plus i.v. post‐administration (5 min later) of STS 1,264 mg/kg, was much greater than that (+13%) seen in the conventional TRC, but BUN level was elevated (44.9 mg/dl). AT‐II (15 μg/kg) administered i.a. simultaneously with CDDP normalized the BUN level (20.3 mg/dl) and further decreased (‐15% to ‐31%) the tumor area (modified TRC). The modified TRC also exhibited a higher anti‐tumor effect than did CDDP 3 mg/kg with AT‐II i.a. (5%) at a similar BUN level (22.2 mg/dl). Loss of body weight, decrease in WBC count and changes in serum transaminases of rats treated with the modified TRC were tolerable. The improved therapeutic effect of the modified TRC was explained as follows: during AT‐ll‐induced hypertension, (1) CDDP delivery to the tumor was increased by 150% and (2) CDDP delivery to the kidney was decreased by 35%. The latter effect of AT‐II made feasible the post‐administration of STS to CDDP.