Genetic polymorphisms of platelet adhesive molecules: association with breast cancer risk and clinical presentation

The main platelet adhesive receptors integrin 21, integrin IIb3 and glycoprotein (GP) Ib are also expressed in breast carcinoma cells. They play a key role in tumor cell-induced platelet aggregation and in adhesive interactions necessary for tumoral invasion and metastasis. Several polymorphisms affecting these molecules, two in integrin 2 (C807T and G1648A), one in integrin 3 (T1565C) and one in GP Ib (VNTR), influencing their levels, structure, and possibly their function, have been previously described and associated with cardiovascular diseases. In this study, we investigated the association of these polymorphisms with breast cancer risk or clinical presentation. We studied 101 patients with invasive breast cancer. The main prognostic variables were recorded, and genomic PCR analysis of these polymorphisms was performed. A group of 101 control subjects matched on age and sex was studied and compared with patients. No association was found between VNTR (GP Ib) polymorphism and breast cancer risk or presentation. Genotype and allele frequencies of C807T and G1648A polymorphisms of integrin 2 were not statistically different in breast cancer patients and controls, although we found an association between the 1648G/G genotype and higher disease stages (III and IV) (p = 0.02). Breast cancer risk was higher in carriers of 3 integrin T/T genotype (OR = 2.08, 95% CI = 1.04–4.16, p = 0.04). Furthermore, genotype 1565T/T was also associated with axillary nodal metastasis (p = 0.017) and with tumoral diameter greater than 2 cm (p = 0.02). Although confirmatory studies are needed, our results suggest that polymorphic genetic variation of integrins expressed in platelets and epithelial breast cells could modify the risk and the biological aggressiveness of breast carcinomas.     

Évaluation de la qualité de vie en oncologie: II—Méthodes

Résumé: Cet article présente les différentes méthodes dévaluation de la qualité de vie: lentretien ouvert, la mesure standardisée au moyen de questionnaires, lévaluation personnalisée, et évoque les avantages et les inconvénients de chacune dentre elles. Dans une deuxième partie est abordée la longue succession détapes indispensables à la construction et à la validation dun questionnaire standardisé de qualité de vie, montrant la nécessité de toujours recourir à lexpertise des patients concernés par la problématique et celle des soignants familiers du domaine. Les problèmes dadaptation et de validation transculturelle de ces outils sont envisagés. Outre lintérêt de ces instruments pour la recherche clinique est envisagée ici la possibilité de recourir aux outils de qualité de vie pour affiner la démarche clinique individuelle, dans le souci permanent dapprofondir notre compréhension des difficultés et des besoins du patient atteint de cancer.Dossier: «Évaluation de la qualité de vie»     

Prognostic relevance of transforming growth factor alpha (TGF-α) and tumor necrosis factor alpha (TNF-α) detected in breast cancer tissues by immunohistochemistry

Summary The function of different growth factors in the development and progression of malignant tumors and the role of cytotoxic cytokines in the host response generated against neoplasms have been recently studied. Anti-TGF- and anti-TNF- monoclonal antibody families have been developed and characterized previously by our laboratory. Libraries of anti-TGF- and anti-TNF- monoclonal antibodies were selected for equal immunoreactivity both in native (frozen) and in formaldehyde fixed, paraffin embedded histological sections. No differences were found between native and fixed samples demonstrated in 10 cases in the present prospective study. Retrospective investigation was performed in 35 histopathological specimens of breast cancer patients detailed clinically and observed during 5 years after the surgical treatment. Correlation between TGF- and/or TNF- expression and clinical staging - TNM score, lymph node metastasis, tumor recurrence and survival time - was analyzed. According to our present study, the TGF- positive patients had worse clinical prognosis than the TNF- positive and double positive cases during long term observation.     

Selective inhibition of cell proliferation and DNA synthesis by the polysulphated carbohydrate ι-carrageenan

-Carrageenan is a polysulphated carbohydrate that antagonises some heparin-binding growth factors. We assessed the effect of -carrageenan on the proliferation of a panel of cell lines, some of which require heparin-binding growth factors for mitogenesis. The importance of growth factor antagonism for the antiproliferative activity was also determined. Cell proliferation was determined by cell counts and a tetrazolium dye (MTT) assay, and DNA synthesis was determined by thymidine incorporation. The proliferation of the basic fibroblast growth factor (bFGF)-dependent endothelial cell line FBHE was inhibited by daily administration of -carrageenan in a dose-dependent manner [concentration inhibiting cell growth by 50% (IC₅₀ value), approx. 0.5 g/ml]. However, excess bFGF did not reverse the inhibitory effect. DNA synthesis was completely inhibited by concentrations of -carrageenan that nonetheless allowed significant protein synthesis to occur. The proliferation of the androgen-dependent prostate-carcinoma cell line LNCaP was also inhibited by -carrageenan (IC₅₀ value, 5.5 g/ml) and the cells were arrested at the G1/S boundary. -Carrageenan inhibited DNA synthesis in MCF-7 cells stimulated by bFGF and transforming growth factor (TGF) but not in those stimulated by insulin-like growth factor 1 (IGF-1). Blocking IGF-1-mediated DNA synthesis with anti-IGF-1 receptor antibody IR3 enhanced the inhibitory activity of -carrageenan against MCF-7 cells grown in serum. A number of other transformed and non-transformed cell lines were either partially inhibited or not inhibited by -carrageenan. -Carrageenan had low anti-coagulant activity. -Carrageenan is a selective anti-proliferative agent and warrants further investigation for anti-angiogenic therapy (in view of its activity against endothelial cells) and for the treatment of androgen-dependent prostate cancer.     

Multiple actions of synthetic ‘progestins’ on the growth of ZR-75-1 human breast cancer cells: Anin vitro model for the simultaneous assay of androgen,progestin, estrogen,and glucocorticoid agonistic and antagonistic activities of steroids

This study was designed to assess the multiple steroid receptor mediated activities of a series of synthetic progestins on breast cancer cell growth, using the human ZR-75-1 cell line which possesses functional estrogen (ER), androgen (AR), and glucocorticoid (GR) receptors as well as progesterone (PgR) receptors. Four 17-hydroxyprogesterone derivatives (chlormadinone acetate, CMA; cyproterone acetate, CPA; medroxyprogesterone acetate, MPA; and megestrol acetate, MGA) and two 19-nortestosterone derivatives (norethindrone, NRE, and norgestrel, NRG) were thus investigated.Based on the requirement of estrogens for PgR-mediated antiproliferative effects and the reversal of PgR-mediated action by insulin, it was found that although all progestins could inhibit ZR-75-1 cell growth through the PgR at low concentrations, the relative contribution of this receptor in cell growth control is highly variable between compounds. The quantitative importance of PgR-mediated inhibition of cell proliferation was inversely related to the amplitude of the androgenic effects induced by the compounds, the AR-mediated effects increasing in the order CPA < MGA < CMA < NRE < NRG < MPA. The specificity of these androgenic effects is further supported by their reversal upon addition of the antiandrogen hydroxyflutamide. In addition, the 17-hydroxyprogesterone derivatives, but not the 19-nortestosterone derivatives, had glucocorticoid activities at high (micromolar) concentrations, as shown by reversal of growth inhibition by the antagonist RU486 in the presence of saturating concentrations of 5-dihydrotestosterone. All progestins tested, except MPA and NRE, also had some antiglucocorticoid activity, NRG being the most potent in this respect. Finally, NRE and NRG exerted a marked mitogenic effect in estrogen-free medium which was clearly mediated through the ER as shown by the competitive reversal of their action by the steroidal antiestrogen EM-139.The present results show that growth measurements of the human breast cancer cells ZR-75-1 permit, with the appropriate steroid additions, the assay of progestin, androgen, estrogen, and glucocorticoid agonistic as vell as antagonistic activities of test compounds. The present study shows, somewhat surprisingly, that while the AR is almost completely responsible for the action of MPA at low concentrations, the majority of the action of NRE, NRG, and MGA is also exerted through AR, while the androgenic action of CPA plays a lower role in the growth inhibition induced by this compound. Such a model should be of great help in designing more specific steroid drugs and in better understanding the role of the different steroid classes which can be used to control the growth of hormone-sensitive cancer. The present data also indicate that progestin is an inappropriate name for MPA, NRE, NRG, MGA, CMA, and CPA, which all possess other and sometimes more potent steroidal activites than those related to interaction with the progesterone receptor.Abbreviations CMA chlormadinone acetate [17-acetoxy-6-chloropregna-4, 6-dien-3, 20-dione] - CPA cyproterone acetate [17-acetoxy-6-chloro-1,2-methylene-pregna-4, 6-dien-3, 20-dione] - DEX dexamethasone [9-fluoro-11, 17, 21-trihydroxy-16-methyl-pregna-1, 4-dien-3, 20-dione] - DHT 5-dihydrotestosterone [17-hydroxy-5-androstan-3-one] - E₂ estradiol [estra-1, 3, 5 (10)-trien-3, 17-diol] - EM 139 [N-n-butyl-N-methyl-11-(16-chloro-3, 17-dihydroxyestra-1, 3, 5 (10)-triene-7-yl) undecanamide] - MGA megestrol acetate [17-acetoxy-6-methylpregna-4, 6-dien-3, 20-dionel] - MPA medroxyprogesterone acetate [17-acetoxy-6-methylpregn-4-en-3, 20-dione] - NRE norethindrone [17-hydroxy-19-nor-17-pregn-4-en-20-yn-3-one] - NRG norgestrel [13-ethyl-17-hydroxy-18, 19-dinor-17-pregn-4-en-20-yn-3-one] - OHF hydroxyflutamide (SCH 16423) [, , -trifluoro-2-methyl-4-nitro-m-lactotoluidide] - R1881 methyltrienolone [17-hydroxy-17-methyl estra-4, 9, 11-trien-3-one] - R5020 promegestone [17, 21-dimethyl-19-norpregna-4, 9-dien-3, 20-dione] - RU486 [17-hydroxy-11-(4-dimethylaminophenyl)-17-(1-propynyl)-estra-4, 9-dien-3-one] - triamcinolone acetonide [9-fluoro-11, 21-dihydroxy-16, 17(1-methylethylidenebis oxy) pregna-1, 4-dien-3, 20-dione]     

A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma

Background:Molecular response is being investigated as atherapeutic goal in follicular lymphoma (FL). High response rates in FL withthe fludarabine combination FMD have been associated with molecularremission. A phase II study of FMD in FL was therefore conducted. Patients and methods:Fifty-four patients, ten of whom were newlydiagnosed received FMD. Forty-four percent of the previously treated patientshad chemoresistant disease. Treatment comprised: fludarabine 25mg/m² days 1–3, mitoxantrone 10 mg/m² day 1, anddexamethasone 20 mg days 1–5. Blood/bone marrow was collected forquantitation of t(14;18) by real-time PCR. Results:The overall response rate was 37 of 54 (69%),complete responses being seen in 11 patients (20%), with no differencebetween newly diagnosed and the previously treated patients. However, theresponse rate in chemosensitive relapse was 84%, compared to44% in patients in whom the last prior regimen had failed. Molecularresponses were seen in 17 of 25 and PCR negativity in 8 of 25, althoughmolecular and clinical responses did not always correlate. Toxicity wasmoderate, 19 patients required admission. However, in 6 of 12 patients,subsequent G-CSF mobilised stem cell harvests failed. Conclusions:FMD was well tolerated but with a lower than expectedresponse rate. Molecular responses were seen in the majority of respondingpatients however, molecular remission was rare.     

TM-1 cells from an established human malignant glioma cell line produce PDGF,TGF-α, and TGF-β which cooperatively play a stimulatory role for an autocrine growth promotion

Summary We have previously established a human malignant glioma cell line, TM-1. TM-1 cells could proliferate in the serum-free medium. In the present study, immunochemical analysis demonstrated that platelet-derived growth factor (PDGF), transforming growth factor (TGF)-, and TGF- are present in the serum-free medium conditioned by growing TM-1 cells. While the cells appeared to possess a single type of binding sites for epidermal growth factor (EGF) with properties comparable to those determined for other tumor cells, the conditioned medium did not contain EGF. PDGF, TGF-, and EGF added exogenously to serum-free media stimulated thymidine incorporation into DNA of TM-1 cells. In addition, antibodies specific for PDGF and TGF- suppressed this activity. These results indicate autocrine and stimulatory roles of PDGF and TGF- for the proliferation of TM-1 cells. As observed for other tumor cells, TGF- by itself weakly suppressed thymidine incorporation by TM-1 cells. However, TGF- employed in combination with TGF- or EGF appeared to stimulate thymidine incorporation, suggesting that a cooperative action of TGF- with different growth factors may be involved in the stimulatory growth regulation at least for TM-1 cells.     

START: A European state-of-the-art on-line instrument for clinical oncologists

START (State-of-the-Art Oncology in Europe), a freely available resource on the Internet, is a European information base of current clinical approaches to human tumours. Its aim is to help clinical oncologists make appropriate clinical decisions by providing them with updated information reflecting state-of-the-art cancer treatment as perceived by the European oncology community. It is based upon contributions from authors and internal reviewers from all over Europe as selected by START's editorial board under the supervision of an advisory board and a scientific committee. Close collaborations with the main European cancer societies are ongoing. An external feedback process augments the mechanisms for rendering START a truly European instrument. START is concerned with evidence-based cancer medicine, and the main clinical options are thus codified and their bases indicated in accord with a scale worked out from the perspective of clinical decision-making. Therapeutic options may be standard, investigational, or suitable for individual clinical use (within the context of a decision made jointly by the patient and the physician). The goal of instruments such as START is to improve the quality of patient care. In addition, START hopes to make contributions to the methodology by which medical research is transformed into clinical decisions.     

Glycogen‐rich carcinomas of the breast display unique characteristics with respect to proliferation and the frequency of oligonucleosomal fragments

We determined the proliferation rate and apoptotic activity of glycogenrich carcinomas of the breast as opposed to nonclear cell tumors by means of MIB1 immunohistochemistry and in situ detection of oligonucleosomal fragments (TUNEL reaction). The retrospective biopsy series included six invasive clear cell carcinomas of the glycogenrich type as well as 15 randomly selected cases of invasive ductal carcinoma without evidence of glycogen storage. Three patients in the clear cell group and seven patients in the control cohort developed lymphnode metastasis. The MIB1 labeling index of glycogenrich carcinomas averaged 9.05%, while that of the controls was 30.03%. Apoptotic nuclei were present in a mean of 1.26% of glycogenrich carcinoma cells. The control tumors exhibited an average apoptotic frequency of 5.85%. Tumor size, hormone receptor status, and presence or absence of lymph node involvement were found not to correlate with either proliferation or apoptosis. We conclude that glycogenrich breast carcinomas are characterized by a peculiar low proliferationlow apoptosis cell kinetic profile. The aggressive clinical behavior of these neoplasms may possibly be accounted for by an ineffective apoptotic elimination of otherwise slowly proliferating tumor cells.     

Ultrastructural Changes of the Vascular Endothelium after Intra-arterial Administration of Tumor Necrosis Factor-alpha (TNFα) in Rat Gliomas

The ensuing ultrastructural changes in tumor vascular endothelial cells following intra-arterial administration of tumor necrosis factor- (TNF) were studied in an experimental rat glioma model. C6 glioma cells were implanted in Wistar rats and then after 14 days, 5×10³U of human natural-type TNF (1.7×10⁵U/m²) was administered through the carotid artery. The animals were sacrificed at 3 or 24h after TNF treatment. A detailed examination with transmission electron microscope revealed swelling of the tumor vascular endothelial cell nuclei and mitochondria with matrix densities at 3h. At 24h, these cells demonstrated the presence of high amplitude mitochondrial swelling or the violent blebbing characteristic of damaged mitochondria; the cytoplasm was swollen enormously and there were dissolution of cytoplasmic organelles and rupture of the plasma membrane. The observed findings were typical of cell necrosis and confirms yet another mechanism by which TNF exerts its anti-tumor effects, that is, necrotizing effects on tumor vascular endothelium. The information appears to be important in the context of clinical application of intra-arterial TNF in the treatment of malignant gliomas.     

Évaluation de la qualité de vie en oncologie: I—Définitions et objectifs

Résumé: En oncologie où lobjectif des traitements porte à la fois sur la quantité et sur la qualité de vie, lévaluation de la qualité de vie savère particulièrement pertinente. Le concept de qualité de vie se définit comme une perception subjective et globale. Son évaluation est multidimensionnelle et déterminée en fonction de définitions opérationnelles. Lévaluation de la qualité de vie permet délargir létude de limpact des traitements aux paramètres autres que biomédicaux, en particulier dans les situations au pronostic réservé ou face à des traitements defficacité équivalente. Les informations issues détudes de qualité de vie vont participer aux prises de décision thérapeutique. Elles se révèlent également utiles à lamélioration de la prise en charge globale du patient atteint de cancer, notamment par lidentification des besoins en soins de support. Cet article situe la problématique de lévaluation du concept de qualité de vie et en présente ses objectifs dans le domaine de loncologie.Dossier: «Évaluation de la qualité de vie»     

A sequential cell kinetic study of meningioma cells in primary explant culture using bromodeoxyuridine

The present study was undertaken to evaluate the sequential BrdU-LI at weekly intervals upto four weeks in 18 primary explant cultures of meningiomas. This revealed three distinct patterns of growth which could be arbitrarily defined as degenerating (group I), proliferating (group II) and adaptive (group III) types. Interestingly two cases of malignant and two of recurrent meningiomas fell into the degenerating group I pattern. The possible explanations for the observed relatively higherin vitro LI values compared to lowerin vivo values as reported in the literature and the theoretical implications of the three distinct patterns of sequential LI values are discussed.     

Cytokine‐regulated urokinase‐type‐plasminogen‐activator (uPA) production by human breast fibroblasts in vitro

It has been shown that, in breast stroma, urokinasetype plasminogen activator (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor environment are candidates responsible for the induction of these uPAproducing myofibroblasts, we studied in vitro the capacity of a paired panel of normal and tumorderived human breast fibroblasts to produce uPA protein and the myofibroblast marker smoothmuscleactin (SMA) in response to various cytokines implicated in the process of tissueremodeling during malignant transformation.We found that fibroblasts produced increased amounts of uPA protein after exposure to aFGF, bFGF, EGF, PDGFBB, and IFN, were unaffected in this respect by IL6, MCSF, GMCSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL1, TNF, IGFI, and IGFII. None of these cytokines were able to induce a striking increase in the fraction of SMApositive fibroblasts. On the other hand, 25pM TGF₁ increased the fraction of SMApositive fibroblasts 5fold in both normal and tumortissuederived fibroblasts. Nonetheless, the normalderived fibroblasts were unaffected in their uPAproducing capacity by TGF₁, and the tumorderived fibroblasts produced decreased amounts of uPA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uPA by human breast fibroblasts. In addition, we established that the basaluPAproduction of both normal and tumorderived fibroblasts was increased by autocrinely produced bFGFlike activity, and that the basaluPAproduction of at least the normalderived fibroblasts was decreased by autocrinely produced IGFlike activity.Altogether, our data suggest an active role for fibroblasts in the process of uPAdirected breast tumor proteolysis.     

On the development of an interstitial radiation protocol for a multicenter consortium. Experience with permanent low-dose rate and temporary high-dose rate125I implants in ‘failed’ and ‘newly diagnosed’ glioblastoma patients: Quality assurance methodology and a possible future adjuvant for therapeutic enhancement

Summary Three interstitial implant trial groups (one permanent low-dose rate¹²⁵I and two temporary high-dose rate¹²⁵I implants) in glioblastoma patients (newly diagnosed and failed) were compared to non-randomized similar control groups for efficacy. The results formed the basis for the BTCG 87-01 national implant trial. The pilot trial demonstrated: 1) the effectiveness of a temporary high-dose rate¹²⁵I implant in failed and newly diagnosed patients; 2) the ability of a multicenter consortium to adhere to a standard protocol; 3) a methodology to insure quality assurance; and 4) the possibility of the future adjuvant application of hyperthermia using a single catheter system.     

Studies on the mechanism of cytotoxicity of 3′-deoxyadenosine N1-oxide in different strains of Ehrlich ascites tumor cells

Summary The correlation between the metabolic processing of 3-deoxyadenosine N ¹-oxide (3-dANO) in vitro and its effect on tumor growth in vivo has been investigated in seven different strains of Ehrlich ascites tumor cells.The metabolism of 3-dANO is initiated by reduction to 3-deoxyadenosine (3-dA). This process is the rate-limiting process. The 3-dA does not accumulate, but is converted to 3-deoxyadenosine triphosphate (3-dATP) or 3-deoxyinosine (3-dI). The ratio between 3-dATP and 3-dI inosine corresponds to the ratio between the activities of adenosine kinase and adenosine deaminase in the cell.Two of the cell lines were markedly inhibited by 3-dANO in vivo. In these cells the accumulation of 3-dATP was 1.4–2.2 nmol/h per mg cells, which accounts for the major part of the metabolized 3-dANO. Five of the cell lines were not inhibited by 3-dANO and the formation of 3-dATP was 5–10 times less in these than in the sensitive strains. The low level of 3-dATP is caused primarily by a low ratio between the activities of adenosine kinase and adenosine deaminase, which is 15 time less than in the sensitive cell lines. The rate of reduction of 3-dANO seems to be of minor importance.These results indicate a correlation between the inhibition of tumor growth by 3-dATP and the ability of the cell to accumulate 3-dATP from 3-dANO and show that this conversion is determined solely by the rate of reduction of 3-dANO (3-dANO reductase activity) and the ratio between the activities of adenosine kinase and adenosine deaminase in the cell. Consequently, the estimation of these enzyme activities in cell lysate of a given tumor can be used to predict whether the tumor is susceptible to inhibition by 3-dANO.Abbreviation 3-dANO 3-deoxyadenosine N ¹-oxide - 3-dA 3-deoxyadenosine - 3-dI 3-deoxyinosine - 3-dATP 3-deoxyadenosine triphosphate This work was supported by The Danish Medical Research Council, Gerda and Åge Haensch Fond, Direktor Åge Henriksens Fond, P. Carl Petersens Fond and the Danish Cancer Society     

Growth inhibitory effect of recombinant α and β interferon on human glioma cells

Summary Growth inhibitory activity of recombinant and interferon on two human glioma cell lines, EFC-2 and KE cells, was determined by two different growth assays. Recombinant interferon showed slight growth inhibitory effect on EFC-2 cells at day 3, and maximum inhibition was seen on day 6 with an ID50 of 50 U/ml. Recombinant interferon showed no significant growth inhibition at any concentration. KE cells were resistant to both recombinant and interferon. The growth inhibitory activity of recombinant interferon on EFC-2 cells was not blocked by recombinant interferon, although recombinant and interferons shared same receptors on EFC-2 cells. Addition of DFMO (-difluoromethylornithine) to interferon in the media showed additive effect rather than synergistic effect in growth inhibition of glioma cells. Out of 7 glioma cell lines tested, 4 showed heterogeneous sensitivity to recombinant interferon, and all were resistant to recombinant interferon. These results suggest differential sensitivity of EFC-2 cells to recombinant interferon, as well as a heterogeneous sensitivity to recombinant interferon among different glioma cell lines.     

Evaluation of response to postradiation eight in one chemotherapy in childhood brain tumors

Ten children, 3 to 15 years of age with high risk primary brain tumors were treated with postradiation eight in one chemotherapy; vincristine, lomustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, cyclophosphamide and methylprednisolone. The tumors comprised of three medulloblastomas, two primitive neuroectodermal tumors, one ependymoblastoma and four anaplastic ependymomas. Treatment involved surgery (two total resection, six subtotal and two biopsy only) followed by conventional radiotherapy (primary tumor: 50–54 Gy, whole brain: 30–45 Gy, and spinal axis: 25–36 Gy). Objective tumor response with radiotherapy was achieved in 7 of 9 patients (78%) (6/8 patients with residual tumor and one patient with complete resection but positive cerebrospinal fluid cytology). Complete response was attained in 4 of 9 patients (44%). Eight in one chemotherapy was initiated four weeks after radiation and repeated at 4 weekly intervals for 5–8 courses. Postradiation eight in one failed to show any additional effect on tumor responses. Median survival was 34 months (range 9–48 months) with five of ten patients alive: four in complete and one in partial remission. All the five survivors were among the patients who had achieved response to initial treatment. This result suggested that degree of response to initial treatment might determine subsequent outcome and thus the choice of modality for initial therapy might be important.     

Effects of scheduling and ascites-associated macrophages on combined antiproliferative activity of alpha-2b interferon and gamma-interferon in a clonogenic assay

Summary Effects of combination treatment with human recombinant alpha-2b interferon (IFN-2b) and gamma interferon (IFN-) and sequencing of the combination on colony formation of human tumor cells were studied in a human tumor clonogenic assay (HTCA) with or without ascites-associated macrophages (AAM). Five different human tumor cell lines were studied. Three of the five cell lines (ovarian cancer cell line BG-1, cervical cancer cell line ME-180, and melanoma cell line SK-MEL 28) were sensitive to both IFNs.Cervical cancer cell line CaSki was sensitive to IFN-2b but resistant to IFN-. Endometrial cancer cell line HEC-1A was resistant to both IFNs. Synergistic interaction was observed in BG-1 and SK-MEL 28 with a combination of the IFNs. ME-180 did not exhibit a positive interaction, in spite of its sensitivity to each IFN. CaSki and HEC-1A also did not exhibit a positive combined interaction at clinically achievable concentrations. One sequential combination method (method 1: IFN-2b IFN gamma with a 24-h interval) resulted in a similar antitumor effect as the simultaneous combination. A reversed sequential method (method 2: IFN- IFN-2b with a 24-h interval) was less effective in three of the five cell lines. In BG-1, AAM enclosed in the lower layer markedly enhanced the antitumor effect of combined IFNs as well as each IFN alone. The antitumor effect with method 1 was significantly greater than that achieved with simultaneous combination or combination according to method 2 in the presence of AAM (P<0.01). These results suggest that (1) a synergistic antitumor effect of IFN-2b and IFN gamma is demonstrable in selected types of tumors, depending upon the sensitivity of each tumor cell line to both IFNs; (2) optimal scheduling for the direct antitumor effect of combined IFNs seems to be long-term exposure of cells to the IFN, the cells being treated with both IFNs either simultaneously or sequentially (IFN-2b preceding IFN-); and (3) AAM potentiate the antitumor effect of IFNs either alone or in combination. Finally, IFN-2b may have some priming effects for the indirect effect of IFN gamma mediated through AAM in certain tumor cells.     

Intermittent Blood Flow in Solid Tumours – an under-appreciated Source of ‘drug Resistance’

As the search for improved anti-cancer drugs continues, new paradigms concerning the reasons for clinical failures in common human solid tumours are also evolving. Classical drug resistance is now perhaps less often invoked to explain lack of treatment efficacy than are newer concepts, including contact resistance, tumour heterogeneity, regrowth resistance, and physiological barriers to drug delivery. This commentary will explore the resistance of solid tumours to chemotherapy from yet another, largely ignored perspective: that of tumour-specific fluctuations in blood flow. Transient decreases in blood flow have significant implications for delivery of chemotherapeutic agents, cellular responsiveness to those agents, and the regrowth potential of the surviving tumour cells.     

Potentiation of the chemotherapeutic action of 5′-deoxy-5-fluorouridine in combination with guanosine and related compounds

Summary The effect of inosine, guanosine, and guanosine 5-monophosphate (GMP) on the antitumor activity of 5-deoxy-5-fluorouridine (5-DFUR) was investigated using P388 leukemia and P815 mastocytoma.The antitumor activity of 5-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILS_max/dose at ILS₃₀) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system.The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.