Adjuvant chemoradiotherapy of advanced resectable rectal cancer: results of a randomised trial comparing modulation of 5-fluorouracil with folinic acid or with interferon-α.

BACKGROUND: Standard adjuvant chemoradiotherapy of rectal cancer still consists of 5-fluorouracil (5-FU) only. Its cytotoxicity is enhanced by folinic acid (FA) and interferon-α (INFα). In this trial, the effects of FA and IFNα on adjuvant 5-FU chemoradiotherapy in locally advanced rectal cancer were investigated. METHODS: Patients with R(0)-resected rectal cancer (UICC stage II and III) were stratified and randomised to a 12-month adjuvant chemoradiotherapy with 5-FU, 5-FU+FA, or 5-FU+IFNα. All patients received levamisol and local irradiation with 50.4 Gy. RESULTS: Median follow-up was 4.9 years (n=796). Toxicities (WHO III+IV) were observed in 32, 28, and 58% of patients receiving 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. No differences between the groups were observed for local or distant recurrence. Five-year overall survival (OS) rates were 60.3% (95% confidence interval (CI): 54.3-65.8), 60.4% (54.4-65.8), and 59.9% (53.0-66.1) for 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. A subgroup analysis in stage II (pT3/4pN0) disease (n=271) revealed that the addition of FA tended to reduce the 5-year local recurrence (LR) rate by 55% and increase recurrence-free survival and OS rates by 12 and 13%, respectively, relative to 5-FU alone. CONCLUSIONS: Interferon-α cannot be recommended for adjuvant chemoradiotherapy of rectal cancer. In UICC stage II disease, the addition of FA tended to lower LR and increased survival. The addition of FA to 5-FU may be an effective option for adjuvant chemoradiotherapy of UICC stage II rectal cancer.

Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment.

AIM: Adjuvant chemotherapy is recommended for stage III colon cancer. The aim of this study was to identify important prognostic factors among patients with colon cancer receiving adjuvant 5-FU-based treatment. METHODS: Data sets of 855 colon cancer patients treated between 1992 and 1999 within a multicenter adjuvant trial comparing 5-FU modulation with folinic acid or interfereron-alpha were examined. Backward elimination in a proportional hazards model was used to identify prognostically relevant clinical and pathological factors. RESULTS: Tumor recurrence (p<0.001), duration of adjuvant treatment (p<0.001), tumor substage (p=0.004), age (p=0.005), grading (p=0.016), treatment-related toxicity (p=0.021), and treatment (p=0.031) were identified in descending order of importance as prognostic factors for overall survival. CONCLUSIONS: Adjuvant 5-FU-based treatment should be performed for at least 6months with a stepwise adjustment of 5-FU doses until toxicity >WHO II. Substages should be reported separately and used for stratification in future trials due to their broad variation in outcome. In the future, this may result in adjuvant treatment of stage III colon cancer adjusted for the risk of substages.

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study.

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial.

BACKGROUND: A weekly continuous 24-h infusion therapy with 5-fluorouracil (5-FU) preceded by a 2-h infusion of calcium folinate (CA-FA) was shown to be an effective first- and secondline treatment in advanced metastatic colorectal cancer. Substitution of CA-FA by the new formulation sodium folinate (S-FA) allows the simultaneous i.v. administration of folinic acid with 5-FU in one pump. PATIENTS AND METHODS: From 1999 to 2001, 42 patients with metastatic colorectal cancer after pre-treatment with a 5-FU bolus regimen were recruited in 5 centres to receive weekly 24-h infusions of 5-FU (2,600 mg/m2) and S-FA (500 mg/m2) dissolved in one pump for 6 weeks as second-line treatment. The treatment cycle was repeated after a 2-week rest period. RESULTS: 106 6-week cycles (median 2, range 1-6 per patient) were administered during the study. The median followup was 22 months. Out of 42 patients, 1 (2%) achieved complete remission, 3 (7%) partial remission, and 31 (74%) no change. Median time to tumour progression was 5.7 months (95% CI: 4.1-6.5). The median survival was reached at 14.7 months (95% CI: 11.0-22.0). Among major toxicities, NCI-CTC grade III/IV diarrhoea occurred in 8/42 (19%), grade III hand-foot-syndrome in 5/42 (12%) and grade III/IV stomatitis in 3/42 (7%) patients. CONCLUSION: Similar to conventional 24-h 5-FU + CA-FA treatment, the combination with S-FA in second-line therapy induced 9% objective responses and stopped tumour progression in 74%. The simultaneous administration of both, S-FA and 5-FU over 24 h dissolved in one pump is convenient, safe and effective as second-line treatment for patients with colorectal cancer.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research.

PURPOSE: The aim of this review is to present the current state of clinical oncological research on mistletoe extracts standardised in terms of the active substance mistletoe lectin. METHODS: This review focuses on studies with clearly defined mistletoe extracts standardised in terms of mistletoe lectins I, II, and III (calculated as mistletoe lectin I, ML I) which belong to the category of rational phytotherapy. That means that studies with anthroposophic or homeopathic drugs will not be included. RESULTS: There are several preclinical studies that show a cytotoxic and immunostimulating effect of mistletoe extracts, predominantly on the cellular immune system. The clinical database, however, is not as good as the experimental results. So far, no direct anticancer action or any improvement in time to tumour progression or overall survival in cancer patients has been seen. The first results of a randomised phase III study suggest that additive administration of a mistletoe preparation may improve the quality of life. CONCLUSION: Mistletoe therapy has not gained an established place in oncology. Further, well-planned randomised clinical investigations will be necessary to verify the first positive findings with regard to an improvement of quality of life in cancer patients.

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer.

BACKGROUND: A weekly continuous 24-hour infusion therapy with 5-fluorouracil (5-FU) and calcium - folinic acid (CA-FA) was shown to be an effective first-line treatment in advanced metastatic colorectal cancer. Sodium - folinic acid (S-FA) is a new formulation which, in contrast to CA-FA allows the simultaneous i.v. administration in combination with 5-FU in one pump. PATIENTS AND METHODS: From 1997 to 1998, 51 patients [median age 60 (range 24-77) years; 38 male, 13 female] with metastatic colorectal cancer were recruited in 5 centers to receive weekly 24-hour infusions of 5-FU (2,600 mg/m(2)) and S-FA (500 mg/m(2)) dissolved in one pump for 6 weeks as first-line treatment. The treatment cycle was repeated after a 2-week rest period. RESULTS: 1,178 administrations (median 24, range 3-54) were performed during the study. Out of 51 patients (median follow-up 20.2 months), 2 (3.9%) achieved complete remission (CR), 17 (33.3%) partial remission (PR), and 21 (41.2%) no change (NC). Progressive disease (PD) was observed in 11/51 (21.6%) patients, including 6 patients who did not complete the first cycle. Median time to tumor progression (TTP) was 8.5 months (95% CI: 5.8-11.3). 32/51 (62.7%) patients survived for more than 1 year, the median survival was reached at 16.5 months (95%CI: 10.2-22.8). Among major toxicities, NCICTC grade III/IV diarrhea occurred in 13/51 (25.4%), grade III hand-foot syndrome in 6/51 (11.7%) patients. Grade III/IV stomatitis was observed in 4/51 (7.8%), cardiac toxicity occurred in 2/51 patients (3.9%). CONCLUSION: Similar to conventional 24-hour 5-FU + CA-FA treatment, the combination with S-FA induced 37.2% objective responses with moderate toxicity. However, TTP seems favorable and the administration of S-FA is convenient, while saving costs and time for the patient in outpatient units.

Cyclophosphamide, adriamycin and dexamethasone (CAD) is a highly effective therapy for patients with advanced multiple myeloma.

BACKGROUND: Patients with advanced multiple myeloma (stage III or progressive myeloma) received the CAD protocol every three weeks: cyclophosphamide 200 mg/m2 i.v./orally days 1-4, adriamycin 30 mg/m2 i.v. on day 1 and dexamethasone 40 mg p.o. days 1-4. PATIENTS AND METHODS: Forty-six patients with a median age of sixty years (range 34-84 years) were enrolled. According to Durie-Salmon 44 patients were in stage III, 2 in stage II; 6 patients had renal insufficiency (stage B). Twenty-three patients were pre-treated at least with melphalane/prednisone. RESULTS: Remission rates were as follows: complete remission 4%, partial remission 70%, minimal change 11%, no change 11%, progressive disease 4%. After an observation time of 14 months the median progression free interval for 33 patients not treated with subsequent high-dose chemotherapy with stem-cell support was more than 14 months. Overall, treatment was well tolerated. After 209 cycles given febrile neutropenia occurred in 11% of cycles including one fatal outcome. Neutropenia or thrombocytopenia grade 3-4 WHO was recorded in 18% and 6% of the cycles, respectively. CONCLUSIONS: This study shows that CAD is an effective regimen with an overall remission rate of 74%. The CAD protocol should be further evaluated in prospective trials.

Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells.

Integrins participate in controlling proliferation and migration. Therefore, changes in integrin expression might be responsible for unrestrained proliferation and invasiveness of tumor cells. Alterations of integrin subunit expression have been observed in human colon carcinoma, especially loss or reduction of the alpha5 subunit, which was observed consistently. The mechanisms responsible for reduction of alpha5 expression and alteration of expression of other integrins are not fully understood. Circumstantial evidence from previous investigations points to an involvement of activated ras oncogenes in repression of integrin expression. The K-ras protooncogene is activated by point mutation in 50% of human colon carcinomas. Thus, we choose an antisense approach for specific inactivation of activated K-ras in the human colon carcinoma cell line SW 480 in order to test whether activated K-ras contributes to changes in integrin expression on colon carcinoma cells. Cell surface expression of the alpha1 and the alpha5 subunit was increased in K-ras antisense transfected clones, cell surface expression of the alpha3 subunit and the alphav subunit was decreased. This shows, in a human system, that activated K-ras is involved in diminishing cell surface expression of the alpha1beta1 collagen/laminin receptor and the alpha5beta1 fibronectin receptor, both of which are implicated in maintenance of a non-transformed phenotype. Moreover, activated K-ras contributes to increased cell surface expression of the alpha3beta1 laminin/collagen/fibronectin receptor and the alphavbeta5 vitronectin receptor, which might play a role in metastatic behavior of tumor cells.

Sequential trimetrexate, 5-fluorouracil and folinic acid are effective and well tolerated in metastatic colorectal carcinoma. The phase II study group of the AIO.

Trimetrexate (TMTX) is a new antifolate which avoids competition for cellular uptake with folinic acid (FA). A regimen of sequential TMTX, FA and 5-fluorouracil (5-FU) has shown efficacy in patients with colorectal cancer. Therefore, we treated 34 previously untreated patients with metastatic colorectal cancer with a weekly chemotherapy regimen consisting of 110 mg/m(2) of TMTX intravenously, then 24 h later 200 mg/m(2) of FA (i.v.) and 500 mg/m(2) of 5-FU (i. v.). Thereafter, 7 doses of oral FA (15 mg) were given at 6-hourly intervals. A treatment cycle consisted of 6 weeks of treatment, then 2 weeks of rest. All patients were treated as outpatients unless complications arose. Thirty-three patients were assessable for tumor response, and all 34 patients were assessable for toxicity. Twelve patients (36%; 95% confidence interval: 25-49%) achieved a partial response. The median duration of response was 8.5 months, and median survival was 14 months. The most common toxicity was diarrhea of grade 3/4, observed in 22% of treatment cycles; this decreased to 8% with early loperamide treatment. Hematologic toxicity was mild. The sequential administration of TMTX, FA and 5-FU is an active regimen in the first-line treatment of metastatic colorectal cancer and warrants further studies.

Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer.

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.

Phosphorylation of p125FAK and paxillin focal adhesion proteins in src-transformed cells with different metastatic capacity.

Hamster fibroblasts transformed by Rous sarcoma virus (RSV) display different metastatic potentials that are associated with specific structural features of the v-src oncoprotein. This diverse metastatic activity could be due to various tyrosine phosphorylation levels of specific src protein substrates. To check this hypothesis, phosphorylation of the FAK and paxillin proteins, involved in signal transduction pathways and known as src protein substrates, was tested. It was shown that FAK and paxillin are hyperphosphorylated in the high metastatic cell lines as compared with the phosphotyrosine level of these proteins found in the low metastatic cell lines. In addition, our data confirm that v-src protein plays a direct role in paxillin phosphorylation.

Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells.

The factors that determine the metastatic behavior of pancreatic tumor cells are incompletely understood. In this study, we first demonstrate differences in adhesion properties, integrin expression and in vivo integrin function in the metastatic tumor cell line PaTu 8988s compared with the non-metastatic cell line PaTu 8988t. Both cell lines were derived from the same original tumor and exhibit identical genetic fingerprints. Using in vitro adhesion assays performed on purified extracellular matrix components, adhesion of PaTu 8988s cells was significantly increased on the basal membrane component laminin and decreased on the interstitial matrix protein fibronectin compared to PaTu 8988t cells. By immunocytochemistry and flow cytometry, and in correspondence with their adhesive properties, the metastatic PaTu 8988s cells did express a distinct pattern of integrin subunits. Laminin-binding integrins alpha6 and beta4 were overexpressed in PaTu 8988s cells. Fibronectin-binding alpha5 integrins were present at higher levels in the non-metastatic PaTu 8988t cells, whereas the beta1 subunit expression did not differ. Adhesion to laminin or fibronectin was specific and was mediated via integrins alpha6beta1 and alpha5beta1, respectively. In addition, metastasis formation in vivo after injection of cells into the tail vein of nude mice was inhibited by preincubation of PaTu 8988s cells with antibodies directed against the integrin alpha6 or beta1. We conclude that alpha6beta1 integrins are overexpressed and functionally active in metastatic human pancreatic carcinoma cells, and participate in metastasis formation probably through binding to the basal membrane component laminin.

Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group.

PURPOSE: To compare mantle-cell lymphomas (MCLs) and follicle-center lymphomas (FCLs) for their features of clinical presentation, response to chemotherapy, and prognosis on the basis of a prospective randomized clinical trial. PATIENTS AND METHODS: Patients with MCL and FCL who entered onto the prospective randomized comparison of cyclophosphamide, vincristine, and prednisone (COP) versus prednimustine and mitoxantrone (PmM) followed by a second randomization for interferon (IFN) maintenance versus observation only. RESULTS: One hundred sixty-five of 234 patients had FCL and 45 of 234 patients had MCL. With FCL, both sexes were equally affected (men, 47%); patients with MCL were predominantly men (78%; P < .0004) and had a higher median age (64 v 53 years; P < .0001). Patients with MCL also had more widespread disease, reflected by the proportion of patients with two or greater extranodal manifestations (43% v 21%; P < .005) and nine or greater involved nodal areas (64% v 45%; nonsignificant [NS]). Response to chemotherapy was significantly lower in patients with MCL (complete remission [CR] + partial remission [PR], 69% v 88%; P < .05) and occurred at a slower pace. Patients with MCL also had a shorter event-free interval (median, 8 v 24 months; P < .0001) and overall survival (median, 28 v 77 months; P < .0001). In both subtypes, however, patients with less than two residual lymphoma manifestations in remission experienced a relatively good prognosis with an estimated 5-year survival of greater than 60% for MCL and greater than 75% for FCL. CONCLUSION: MCL and FCL differ substantially in their features of presentation, response to chemotherapy, and long-term prognosis. The extent of residual disease after completion of chemotherapy discriminates patients with different prognosis and may be used for the stratification of postremission strategies.

De novo expression of the alpha5beta1-fibronectin receptor in HT29 colon-cancer cells reduces activity of C-SRC. Increase of C-SRC activity by attachment on fibronectin.

Changes in integrin expression during malignant transformation have been observed in many tumors. Colon-carcinoma cells show reduced expression or even loss of the alpha5beta1 integrin compared to normal or adenoma cells. To determine the significance of absent alpha5beta1 integrin signaling, we transfected the cDNA coding for the alpha5 integrin sub-unit into the human colon-carcinoma cell line HT29, which constitutively lacks this subunit but does express the beta1 subunit. We show here that the newly expressed fibronectin receptor alpha5beta1 generates multiple signals, causing marked changes in cytoskeletal arrangements within a few minutes of adhesion to fibronectin. Cells expressing the alpha5beta1 integrin exhibit the formation of actin stress fibers and focal adhesions, as well as the induction of tyrosine phosphorylation of several proteins, within 10 min. We identified the focal adhesion kinase pp125FAK and the cytoskeletal protein paxillin as major phosphorylation substrates in these cells. These proteins remained hypophosphorylated when alpha5-negative control cells were plated on fibronectin. The tyrosine kinase pp60c-src, regarded as central in the regulation of cellular proliferation and constitutively over-expressed in HT29 and in colon-carcinoma cells, showed reduced intrinsic kinase activity in unstimulated HT29alpha5 cells. In contrast, fibronectin-induced signaling through alpha5beta1 increased pp60c-src activity. Moreover, immunoprecipitation of pp60c-src from extracts of HT29alpha5 cells cultivated on fibronectin for 20 min revealed complex formation of pp60c-src and tyrosine-phosphorylated pp125FAK. Our data suggest that de novo expression of the alpha5beta1 integrin in HT29 colon-cancer cells restores signaling via pp125FAK and pp60c-src. Thus, loss of this receptor during malignant transformation may contribute to tumor-cell autonomy, while reduced activity of pp60c-src in HT29alpha5-cells may participate directly in growth control.

Integrin alpha5beta1: a potent inhibitor of experimental lung metastasis.

The integrin alpha5beta1 seems to be the most relevant receptor of tumor cells for binding to fibronectin. Although numerous studies suggest a role of tumor cell fibronectin interaction in tumor metastasis, differential integrin expression on tumor cells has, however, not been correlated with metastatic capabilities. We addressed this question by transfection of the integrin alpha5beta1 cDNA into HT-29 human colon carcinoma cells which led to de novo expression of functional integrin alpha5beta1. Similar to other reports, expression of the integrin alpha5beta1 in HT-29 tumor cells exerted an inhibitory action on cell proliferation as indicated in our study by formation of fewer colonies in soft agar. The tumor growth inhibitory property of the integrin alpha5beta1 was also shown by reduction of subcutaneous xenograft growth in nude mice to approximately 50% of that of control transfectants. For the first time, we found that several clones of integrin alpha5 subunit transfectants displayed dramatically reduced formation of lung colonies and cutaneous metastasis after intravenous injection into nude mice. While most animals inoculated with control transfectant cells formed macroscopically visible lung colonies ranging from 12.6 +/- 2.6 to 22.0 +/- 6.6 (mean colony number +/- SEM), mice inoculated with HT-29 cell clones expressing the integrin alpha5beta1 were almost completely free of lung colonies (ranging from 0.0 +/- 0 to 0.2 +/- 0.1). Our results imply that integrin alpha5beta1 expression inhibits circulating tumor cells in pursuing late steps of the metastatic process as represented by the artificial metastasis (lung colonisation) model.

Dose intensity phase I/II trial with carboplatin, ifosfamide, etoposide and vincristine combined with filgrastim in patients with small-cell lung cancer.

BACKGROUND: The purpose of the study was to evaluate the feasibility of increasing dose intensity by a stepwise reduction of the time intervals between chemotherapy cycles in separate patient cohorts with small-cell lung cancer. Patients received up to 6 courses of combination chemotherapy with carboplatin, etoposide, ifosfamide and vincristine followed by support with filgrastim. Dose intensity, incidence, duration and severity of neutropenic fever and infections, objective response to chemotherapy, and safety of filgrastim were determined. PATIENTS AND METHODS: 29 patients with small-cell lung cancer (limited disease: 2, extensive disease: 27) were treated with a combination of carboplatin 250 mg/m2 i.v. day 1, ifosfamide 2 g/m2 and etoposide 120 mg/m2 i.v. days 1 and 2, etoposide 120 mg/m2 orally day 3, and vincristine 1.4 mg/m2 day 14. Initially, filgrastim (5 micrograms/kg) was administered subcutaneously from day 7 to 16. With shorter treatment intervals, filgrastim was administered on days 4-16 or 4-14. RESULTS: An overall increase in dose intensity by a factor of 1.44 was achieved after reducing the treatment interval from 27 to 17 days. Further reduction to 14 days was not feasible due to persistent thrombocytopenia. Six patients (21%) developed a total of 9 febrile episodes, and 14 patients (48%) had to be withdrawn from the study before the completion of six cycles of chemotherapy. The median duration of infectious episodes was 6 days. Overall, a total of 22 of 27 evaluable patients had an objective response. Longer treatment intervals resulted in a lower probability for objective response (> or = 23 days: 10/14 patients vs. < or = 17 days: 7/7 patients). CONCLUSION: Filgrastim allows for the reduction of treatment intervals in patients with small-cell lung cancer and increased dose intensity with acceptable hematologic and nonhematologic toxicities.

Prothymosin alpha 1 effects, in vitro, on the antitumor activity and cytokine production of blood monocytes from colorectal tumor patients.

Recent animal studies demonstrate that prothymosin alpha 1 (ProT alpha) enhances the antitumor response by stimulation of mononuclear phagocyte functions. The present study was aimed at characterizing the in vitro effects by ProT alpha on blood monocytes from human colon cancer patients. Purified peripheral blood monocytes were studied in terms of tumor cytostatic ability and cytokine production after incubation with ProT alpha or interferon (rIFN-gamma) and transforming growth factor-beta (TGF beta), used as reference substances. SW620 colon carcinoma cells were used as tumor target cells in growth inhibition experiments. The level of baseline growth inhibitory activity of unstimulated patient's monocytes was significantly lower than that of normal monocytes. The defective antitumor activity of patient monocytes was associated with a higher production of the inhibitory monokines prostaglandin E2 (PGE2) and TGF beta. The stimulation of monocytes by ProT alpha and/or rIFN-gamma elevated the average antitumor activity in all donor groups. The ProT alpha-induced increase was associated with a significantly higher monocytic secretion of IL-1 beta and TNF-alpha. Moreover, the concentrations of TGF beta and PGE2 in the culture supernatants decreased significantly, when patient's monocytes were treated with ProT alpha and/or rIFN-gamma. Additionally, ProT alpha enhanced the diminished antitumor activity of TGF beta-treated normal monocytes. These results suggest that ProT alpha selectively regulates distinct functions of blood monocytes, the effect of this cytokine varying with the parameter and donor population examined. These data provide a rational and biological endpoint for further studies with ProT alpha as an activator of mononuclear function in colon cancer.