ABSTRACT
BACKGROUND: Lenalidomide has immunomodulatory and anti-angiogenic effects and showed moderate anti-tumour efficacy in patients with. advanced hepatocellular carcinoma (HCC) AIM: To explore potential biomarkers of lenalidomide efficacy as second-line therapy for HCC. METHODS: Eligible patients were diagnosed with advanced HCC, documented progression on sorafenib, and Child-Pugh class A liver function. Patients received 25 mg/day lenalidomide orally on days 1-21 every 4 weeks. The primary endpoint was 6 month progression-free survival rate. Early α-fetoprotein response was defined as a > 20% decline of α-fetoprotein levels from baseline within the first 4 weeks of treatment. Vascular response, evaluated using dynamic contrast-enhanced magnetic resonance imaging, was defined as a > 40% decline in Ktrans after 2 weeks of treatment. The percentage of peripheral blood lymphocyte subsets were also analysed. RESULTS: Fifty-five patients were enrolled. The response rate was 13%, and the disease-control rate was 53%. The 6 month progression-free survival rate was 9.1%. The median progression-free and overall survival was 1.8 months and 8.9 months respectively. Early α-fetoprotein response was significantly associated with higher disease-control rate (76% vs 22%, P = .001) and longer progression-free survival (P = .020). Vascular response was not associated with any treatment outcomes. Patients with a high pre-treatment B cell percentage were more likely to have disease control (70% vs 36%, P = .010) and exhibited longer progression-free survival (P < .001) and overall survival (P = .042). CONCLUSIONS: Lenalidomide exhibited moderate activity as second-line therapy for advanced HCC. Its immunomodulatory effects should be further explored (www.clinicaltrials.gov NCT01545804).
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/adverse effects , Biomarkers, Tumor/metabolism , Disease Progression , Disease-Free Survival , Female , Humans , Lenalidomide , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Sorafenib , Thalidomide/administration & dosage , Treatment Outcome , alpha-Fetoproteins/metabolismABSTRACT
Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.
Subject(s)
Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Helicobacter Infections , Helicobacter pylori , Interleukins , Lymphoma, B-Cell, Marginal Zone , Neoplasm Proteins , Polymorphism, Single Nucleotide , Stomach Neoplasms , CD4-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Female , Helicobacter Infections/genetics , Helicobacter Infections/metabolism , Helicobacter Infections/therapy , Humans , Interleukins/biosynthesis , Interleukins/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, B-Cell, Marginal Zone/metabolism , Lymphoma, B-Cell, Marginal Zone/microbiology , Lymphoma, B-Cell, Marginal Zone/therapy , Male , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/microbiology , Stomach Neoplasms/therapy , Interleukin-22ABSTRACT
We prospectively investigated the efficacy and safety of combining weekly vinorelbine (VNB) with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with advanced breast cancer (ABC). Vinorelbine 25 mg m(-2) 30-min intravenous infusion, and high-dose 5-FU 2600 mg m(-2) plus LV 300 mg m(-2) 24-h intravenous infusion (HDFL regimen) were given on days 1 and 8 every 3 weeks. Between June 1999 and April 2003, 40 patients with histologically confirmed recurrent or metastatic breast cancer were enrolled with a median age of 49 years (range: 36-68). A total of 25 patients had recurrent ABC, and 15 patients had primary metastatic diseases. The overall response rate for the intent-to-treat group was 70.0% (95% CI: 54-84%) with eight complete responses and 20 partial responses. All 40 patients were evaluated for survival and toxicities. Among a total of 316 cycles of VNB-HDFL given (average: 7.9: range: 4-14 cycles per patient), the main toxicity was Gr3/4 leucopenia and Gr3/4 neutropenia in 57 (18.0%) and 120 (38.0%) cycles, respectively. Gr1/2 infection and Gr1/2 stomatitis were noted in five (1.6%) and 59 (18.7%) cycles, respectively. None of the patients developed Gr3/4 stomatitis or Gr3/4 infection. Gr2/3 and Gr1 hand-foot syndrome was noted in two (5.0%) and 23 (57.5%) patients, respectively. Gr1 sensory neuropathy developed in three patients. The median time to progression was 8.0 months (range: 3-25.5 months), and the median overall survival was 25.0 months with a follow-up of 5.5 to 45+ months. This VNB-HDFL regimen is a highly active yet well-tolerated first-line treatment for ABC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Middle Aged , Prospective Studies , Vinblastine/administration & dosage , VinorelbineABSTRACT
To investigate the efficacy and safety of combining weekly oxaliplatin with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and folinic acid (FA) in treatment of patients with advanced gastric cancer. Patients with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Oxaliplatin 65 mg m(-2) 2-h intravenous infusion, and 5-FU 2600 mg m(-2) plus FA 300 mg m(-2) 24-h intravenous infusion, were given on days 1 and 8, repeated every 3 weeks. Between January 2001 through January 2002, 55 patients were enrolled. The median age was 64 years (range: 22-75). In all, 52 patients (94.5%) had recurrent or metastatic disease and three patients had locally advanced disease. Among 50 patients evaluable for tumour response, 28 patients achieved partial response, with an overall response rate of 56% (95% confidence interval (CI): 41.8-70.3%). All 55 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 5.2 and 10.0 months, respectively, during median follow-up time of 24.0 months. Major grades 3-4 toxicities were neutropenia in 23 cycles (7.1%) and thrombocytopenia in 16 cycles (5.0%). Treatment was discontinued for treatment-related toxicities in nine patients (16.4%), of whom eight were due to oxaliplatin-related neurotoxicity. One patient (1.8%) died of neutropenic sepsis. This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. Except for neurotoxicity that often develops after prolonged use of oxaliplatin, the regimen is well tolerated.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Leucovorin/administration & dosage , Male , Middle Aged , Nervous System/drug effects , Neutropenia/chemically induced , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Stomach Neoplasms/pathology , Survival Analysis , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
Both gemcitabine and weekly 24-h infusion of high-dose 5-fluorouracil/leucovorin (HDFL) have shown promising antitumour activity for patients with locally advanced or metastatic carcinoma of the biliary tract (CBT). From April 1999 through December 2002, 30 patients with inoperable CBT were treated with gemcitabine 800 mg m(-2), intravenous infusion for 30 min, followed by 5-FU, 2000 mg m(-2) and leucovorin, 300 mg m(-2), intravenous infusion for 24 h, on day 1, 8 and 15, every 4 weeks. A total of 166 cycles were given (median of four cycles per patient, range 1-24 cycles). Response was evaluable in 28 patients and toxicity in 29 patients. Partial response was obtained in six patients, stable disease in 13, while progressive disease occurred in nine. The objective response rate was 21.4% (95% CI: 5.2-37.6%). The most common grade 3 or 4 toxicity was infection (nine patients). Other types of grade 3 or 4 toxicity included leucopenia (four patients), thrombocytopenia (three patients), anaemia (three patients), nausea/vomiting (two patients) and elevation of liver transaminases (three patients). As of 30 September 2003, the median progression-free survival was 3.7 months (95% CI: 2.8-4.6 months) and the median overall survival was 4.7 months (95% CI: 0.8-8.6 months). Our data suggest that weekly gemcitabine plus HDFL is modestly active with acceptable treatment-related toxicity for patients with advanced CBT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biliary Tract Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biliary Tract Neoplasms/mortality , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Disease Progression , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Infusions, Intravenous/adverse effects , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Maximum Tolerated Dose , Middle Aged , Survival Analysis , Treatment Outcome , GemcitabineABSTRACT
BACKGROUND: The aim of the present study was to identify the clinicopathological and molecular biological characteristics of early-onset colorectal cancers. METHODS: The clinicopathological and molecular biological parameters of 138 consecutive patients with colorectal cancer aged less than 40 years were compared with those of 339 patients aged 60 years or more. RESULTS: The younger patients with colorectal cancer had more mucin-producing (14.5 versus 4.7 per cent; P < 0.001) and poorly differentiated (7.2 versus 3.3 per cent; P = 0.015) tumours, a higher incidence of synchronous (5.8 versus 1.2 per cent; P = 0.007) and metachronous (4.0 versus 0.6 per cent; P = 0.023) colorectal cancers, and more advanced tumour stage (P < 0.001) than older patients. The operative mortality rate was lower (0.7 versus 5.0 per cent; P = 0.026), and cancer-specific survival was similar (in stage I, II and III disease; P > 0.05) or better (in stage IV disease; 95 per cent confidence interval 22.50 to 28.41 versus 12.61 to 17.05 months; P < 0.001). There was a higher percentage of normal p53 expression (61.1 versus 46.8 per cent; P = 0.023) and high-frequency microsatellite instability (MSI-H) (29.4 versus 6.3 per cent; P < 0.001), and a similar family history of cancer (17.5 versus 14.2 per cent; P > 0.05), compared with older patients. CONCLUSION: Young patients with colorectal cancer have several distinct clinicopathological and molecular biological features. The mechanisms underlying the inconsistency between the presence of MSI-H and a family history of cancer in these early-onset colorectal cancers deserve further investigation.
Subject(s)
Colorectal Neoplasms/genetics , Genes, DCC/genetics , Genes, p53/genetics , Genes, ras/genetics , Adolescent , Adult , Age Factors , Antimetabolites, Antineoplastic/therapeutic use , Chemotherapy, Adjuvant , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Combined Modality Therapy , Female , Fluorouracil/therapeutic use , Humans , Male , Microsatellite Repeats/genetics , Middle Aged , Neoplasm Staging , Pedigree , Polymerase Chain Reaction/methodsABSTRACT
Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Bowen's Disease/drug therapy , Carcinoma, Transitional Cell/drug therapy , Curcumin/therapeutic use , Leukoplakia, Oral/drug therapy , Precancerous Conditions/drug therapy , Skin Neoplasms/drug therapy , Stomach Neoplasms/prevention & control , Stomach/pathology , Urinary Bladder Neoplasms/drug therapy , Uterine Cervical Dysplasia/drug therapy , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/pharmacokinetics , Arsenicals/adverse effects , Bowen's Disease/chemically induced , Curcumin/administration & dosage , Curcumin/adverse effects , Curcumin/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Male , Metaplasia , Middle Aged , Neoplasm Recurrence, Local/prevention & control , Prospective Studies , Risk , Skin Neoplasms/chemically induced , Treatment OutcomeABSTRACT
We have recently demonstrated that HDFL (high-dose 5-FU 2600 mg m-2 week-1 and leucovorin 500 mg m-2 week-1, weekly 24-h infusion) is highly active in the treatment of gastric cancer. To further clarify the possible mechanism underlying the improved activity of HDFL compared with conventional 5-FU regimens, we conducted in vitro studies examining the effect of these regimens on the differential regulation of thymidylate synthase (TS) in NCI-N87, a human gastric cancer cell line. The expected serum concentrations of 5-FU are 100-200 mM (lasting for less than 30 min) and 5-10 mM (lasting for 24 h) for the conventional 5-FU regimens (bolus injection or short intravenous infusion of 5-FU 370-500 mg m-2) and the HDFL regimens, respectively. Western blot analysis revealed that 24-h exposure of NCI-N87 to 2.5-10.0 mM of 5-FU resulted in a dose-dependent depletion of free TS, lasting for more than 24 h. In contrast, 30-min exposure of NCI-N87 to 200 mM of 5-FU resulted in a less than 12-h depletion of free TS. Moreover, 24-h exposure to 5-FU resulted in a higher S-phase blockade and enhanced cytotoxicity. In both modes of 5-FU treatment, the initial rapid depletion of free TS was accompanied by a rapid increment of a higher-molecular-weight TS molecule, suggesting that rapid formation of the ternary complex was the key mechanism of 5-FU action during this period. Northern blot analysis showed that the steady-state mRNA of TS was not affected by either of the schedules. We conclude that 24-h exposure of gastric cancer cells to low concentration of 5-FU resulted in better suppression of free TS, a higher degree of S-phase blockade, and enhanced cytotoxicity compared to 30-min exposure to high concentration of 5-FU. These in vitro results may help explain the improved clinical efficacy of HDFL regimens compared to conventional 5-FU regimens.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Fluorouracil/administration & dosage , Thymidylate Synthase/antagonists & inhibitors , Blotting, Northern , Cell Cycle/drug effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , RNA, Messenger/metabolism , Stomach Neoplasms/drug therapy , Stomach Neoplasms/enzymology , Thymidylate Synthase/biosynthesis , Thymidylate Synthase/genetics , Tumor Cells, CulturedABSTRACT
Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.
Subject(s)
Cell Cycle Proteins/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Curcumin/therapeutic use , Liver/metabolism , Animals , Blotting, Western , CDC2 Protein Kinase/antagonists & inhibitors , CDC2 Protein Kinase/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/prevention & control , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/drug effects , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Diethylnitrosamine/toxicity , Hyperplasia/drug therapy , Hyperplasia/prevention & control , Liver/drug effects , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/prevention & control , Male , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Oncogene Protein p21(ras)/antagonists & inhibitors , Oncogene Protein p21(ras)/metabolism , Organ Size/drug effects , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Wistar , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolismABSTRACT
Metaplastic carcinoma of the breast is a rare form of breast cancer and has an uncertain prognostic significance. Cases from Asian countries have never been reported in the English literature. Between 1983 and 1998, we encountered 8 cases in our institution. There were 7 women and one man with a median age of 52.5 (37-73) years. Pathologic diagnosis included three poorly-differentiated adenosquamous carcinomas, two adenocarcinomas with spindle cell metaplasia, two matrix-producing carcinomas and one carcinosarcoma. Estrogen receptor was positive in 2 (25%) patients. Local recurrence or distant metastasis developed in 3 patients within one year of initial treatment. With a mean follow-up of 81 months (range, 19-183 months), 5 patients were disease-free at the time of this report. Interestingly, two of our patients had presented with huge-sized inflammatory breast cancer and were refractory to neo-adjuvant chemotherapy, but enjoyed an unexpected long disease-free survival after mastectomy. Although the clinical course of our patients appeared in general similar to that of the Western series, the two patients with inflammatory breast carcinoma ran a very unusual course, which may deserve further characterization.
Subject(s)
Adenocarcinoma/pathology , Breast Neoplasms/pathology , Adenocarcinoma/chemistry , Adenocarcinoma/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Breast Neoplasms, Male/chemistry , Breast Neoplasms, Male/pathology , Breast Neoplasms, Male/therapy , Carcinoma, Adenosquamous/chemistry , Carcinoma, Adenosquamous/pathology , Carcinoma, Adenosquamous/therapy , Carcinoma, Ductal, Breast/chemistry , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/therapy , Carcinosarcoma/chemistry , Carcinosarcoma/pathology , Carcinosarcoma/therapy , Chemotherapy, Adjuvant , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Estrogens , Female , Fluorouracil/administration & dosage , Humans , Inflammation , Lymphatic Metastasis , Male , Mastectomy , Metaplasia , Middle Aged , Neoplasm Metastasis , Neoplasm Proteins/analysis , Neoplasms, Hormone-Dependent/chemistry , Neoplasms, Hormone-Dependent/pathology , Neoplasms, Hormone-Dependent/therapy , Progesterone , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Retrospective Studies , Taiwan/epidemiology , Treatment OutcomeABSTRACT
Curcumin has been widely used as a spice and coloring agent in foods. Recently, curcumin was found to possess chemopreventive effects against skin cancer, forestomach cancer, colon cancer and oral cancer in mice. Clinical trials of curcumin for prevention of human cancers are currently ongoing. In this study, we examine the chemopreventive effect of curcumin on murine hepatocarcinogenesis. C3H/HeN mice were injected i.p. with N-diethylnitrosamine (DEN) at the age of 5 weeks. The curcumin group started eating 0.2% curcumin-containing diet 4 days before DEN injection until death. The mice were then serially killed at the scheduled times to examine the development of hepatocellular carcinoma (HCC) and changes in intermediate biological markers. At the age of 42 weeks, the curcumin group, as compared with the control group (DEN alone), had an 81% reduction in multiplicity (0.5 versus 2.57) and a 62% reduction in incidence (38 versus 100%) of development of HCC. A series of intermediate biological markers were examined by western blot. While hepatic tissues obtained from the DEN-treated mice showed a remarkable increase in the levels of p21(ras), PCNA and CDC2 proteins, eating a curcumin-containing diet reversed the levels to normal values. These results indicate that curcumin effectively inhibits DEN-induced hepatocarcinogenesis in the mouse. The underlying mechanisms of the phenomenon and the feasibility of using curcumin in the chemoprevention of human HCC should be further explored.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Carcinogens/toxicity , Curcumin/therapeutic use , Diethylnitrosamine/toxicity , Liver Neoplasms, Experimental/prevention & control , Liver/drug effects , Spices , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Biomarkers , CDC2 Protein Kinase/analysis , Chemical and Drug Induced Liver Injury/prevention & control , Curcumin/pharmacology , Diet , Liver/chemistry , Liver Neoplasms, Experimental/chemically induced , Male , Mice , Mice, Inbred C3H , Neoplasm Proteins/analysis , Proliferating Cell Nuclear Antigen/analysis , Proto-Oncogene Proteins p21(ras)/analysisABSTRACT
Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.
Subject(s)
Antimetabolites, Antineoplastic/toxicity , Fluorouracil/toxicity , Granulocytes/drug effects , Hematopoietic Stem Cells/drug effects , Monocytes/drug effects , Adolescent , Adult , Antimetabolites, Antineoplastic/administration & dosage , Breast Neoplasms/blood , Colony-Forming Units Assay , Dose-Response Relationship, Drug , Female , Fluorouracil/administration & dosage , Humans , Leukemia, Myeloid/blood , Lymphoma/blood , Male , Middle AgedABSTRACT
High-dose therapy followed by peripheral blood stem cell (PBSC) support was performed in 29 patients with primary high-risk (Group I) or chemoresponsive metastatic (Group II) breast cancer patients. Group I patients had received PBSC mobilization within 4 weeks of modified radical mastectomy. Group II patients had to achieve minimal residual disease (MRD) by induction chemotherapy before being considered eligible for PBSC mobilization and high-dose therapy. An innovative FE120C regimen (5-FU 600 mg/m2, i.v., day 1; epirubicin 120 mg/m2, i.v., day 1; cyclophosphamide 600 mg/m2, i.v., day 1) plus G-CSF (300 microg/day, subcutaneous injection for 9 days, from day 4 post-FE120C) was used to mobilize PBSCs. After high-dose CTCb (cyclophosphamide 6,000 mg/m2, thiothepa 500 mg/m2, carboplatin 800 mg/m2, in 4 days), patients received PBSC infusion and daily C-CSF 300 microg subcutaneous injection. There were 19 and 16 patients enrolled into Group I and Group II, respectively. Ten of the Group II patients had achieved minimal residual disease (MRD) after induction chemotherapy. The median numbers of mobilized total CD34 + cells for Group I and Group II patients were 27.3 (9.2 to 114.1) x 10(6)/kg and 17.1 (5.9 to 69.1) x 10(6)/kg respectively. The median time to neutrophil recovery (ANC > or = 500/microL) was 8 and 9 days in Group I and II, respectively. The median time to platelet recovery (> or = 50,000/microL) was 10 and 15 days in Group I and II, respectively. No major treatment-related toxicities were noted. In Group I, 13 out of 19 patients (68.4%; 43-87%, 95% C.I.) remained recurrence-free with a median follow-up of 31 months (6 + to 55 + months). In Group II, 3 out of 10 patients (30%; 7-65%, 95% C.I.) remained progression-free at 33 +, 35 +, 39 + months from induction therapy. We suggest that the FE120C plus G-CSF is an effective and innovative regimen for PBSC mobilization in breast cancer patients, and high-dose CTCb therapy with PBSC support is a safe and well-tolerated treatment modality.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Adult , Breast Neoplasms/mortality , Clinical Protocols , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Mastectomy, Modified Radical , Middle Aged , Radiotherapy, Adjuvant , Recurrence , Survival RateABSTRACT
We have previously shown that weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL), a regimen initially designed for the treatment of advanced colorectal cancer, is also effective in the treatment of gastric cancer. This HDFL regimen is unique in that it is virtually non-myelosuppressive, and thus provides a comerstone on which ideal protocols may be developed. In this prospective phase II study, we examined the efficacy and toxicity of PE (cisplatin, etoposide)-HDFL, a HDFL-based combination chemotherapy, in the treatment of advanced-gastric cancer. This regimen consisted of cisplatin 60 mg/m2, i.v., D1; etoposide 65 mg/m2, i.v., D1-3; and 5-fluorouracil 2600 mg/m2 plus leucovorin 300 mg/m2, 24-hour i.v. infusion by an ambulatory infusion pump, D2,9,16; repeated every 4 weeks. The major eligibility criteria of the patients included: a) a histologically confirmed, objectively measurable, recurrent or primary inoperable gastric adenocarcinoma; b) age > or = 75 years; c) a Karnofsky performance status > or = 50%; d) an absolute granulocyte count (AGC) > or = 2000/mm3, and a platelet count > or = 100,000/mm3; e) a serum bilirubin concentration < or = 2.0 mg/dl; f) a serum creatinine concentration < or = 1.5 mg/dl; and g) a signed informed consent. Between March 1992 and June 1996, a total of 42 patients were enrolled onto the study. There were 31 men and 11 women with a median age of 54 (24-75) years; these included 16 primary metastatic, 3 locally advanced and inoperable, and 23 postgastrectomy recurrent gastric cancer patients. ECOG (Eastern Cooperative Oncology Group) grade III/IV leukopenia and thrombocytopenia developed in 34.0% and 11.0% of a total of 229 courses given, respectively. There was no treatment-related death. Four patients developed a reversible neurotoxicity; and two of them refused further chemotherapy. Among the 40 patients evaluable for responses, 9 [22.5%; 12-38%, 95% confidence interval (C.I.)] patients achieved complete remission, and 20 [50.0%; 33-67%, 95% C.I.] patients achieved partial remission. The overall response rate was 72.5% [56-86%, 95% C.I.]. The overall median survival and median time to progression of the responders were 10 and 7 months, respectively. The overall median survival of the whole group was 9 months. We concluded that PE-HDFL is a highly effective treatment for advanced gastric cancer. The treatment-related toxicity was mild and the patients' compliance was satisfactory.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/mortality , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Drug Administration Schedule , Etoposide/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Infusion Pumps , Infusions, Intravenous , Leucovorin/administration & dosage , Male , Middle Aged , Patient Compliance , Stomach Neoplasms/mortalityABSTRACT
BACKGROUND: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy. METHODS: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression. RESULTS: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test). CONCLUSIONS: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/enzymology , Antimetabolites, Antineoplastic/therapeutic use , Fluorouracil/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/enzymology , Thymidylate Synthase/biosynthesis , Adult , Aged , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Female , Humans , Immunohistochemistry , Infusions, Intravenous , Male , Middle AgedABSTRACT
Acute disseminated intravascular coagulation (DIC) is a severe complication of gastric adenocarcinoma, and most of the patients die within 1-3 weeks. We have treated five such patients with an empirical non-myelosuppressive HDFL regimen (weekly 24h infusion of high-dose 5-fluorouracil 2600 mg/m2 and leucovorin 300 mg/m2). Within 2 weeks of starting the treatment the clinical and laboratory evidence of acute DIC quickly resolved in all five patients. HDFL not only caused no further myelosuppression, but also resulted in normalization of the patient's haemogram within a few weeks. Other anti-cancer drugs could then be safely added. Three patients had a survival time of more than 6 months. We suggest that HDFL is an ideal initial treatment for gastric cancer complicated by acute DIC.
Subject(s)
Antidotes/administration & dosage , Antimetabolites, Antineoplastic/administration & dosage , Disseminated Intravascular Coagulation/etiology , Fluorouracil/administration & dosage , Leucovorin/administration & dosage , Stomach Neoplasms/complications , Adult , Aged , Disease-Free Survival , Disseminated Intravascular Coagulation/drug therapy , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Stomach Neoplasms/drug therapy , Survival Analysis , Thrombocytopenia/drug therapy , Treatment OutcomeABSTRACT
Hepatocellular carcinoma (HCC) is characterized by high drug resistance to currently available chemotherapeutic agents. In a prospective clinical study, we have demonstrated that high-dose tamoxifen significantly enhanced the therapeutic efficacy of doxorubicin in patients with far-advanced HCC. In a search for a possible mechanism, we found that tamoxifen at a clinically achievable concentration (2.5 microM) significantly enhanced doxorubicin-induced cytotoxicity and apoptosis of Hep-3B cells, a multidrug resistance (MDR)-1 expressing HCC cell line. This synergistic cytotoxic effect of tamoxifen, at this concentration, however, was not mediated by MDR inhibition. Instead, as evidenced by both western blot and immunofluorescence studies, tamoxifen inhibited the cytoplasmic-membrane translocation of protein kinase C (PKC)-alpha. 12-O-Tetradecanoylphorbol-13-acetate (TPA) restored the membrane translocation of PKC-alpha and abrogated the synergistic cytotoxicity of tamoxifen. We also showed that tamoxifen, at this concentration, did not directly affect the enzyme activity of PKC. Further, membrane translocation of other membrane-bound proteins, such as Ras protein, was similarly inhibited by tamoxifen, but could not be restored by the addition of TPA. Together, these data suggested that tamoxifen may act on the cytoplasmic membrane, and thereby inhibit PKC-alpha translocation to the membrane where it is activated. We hypothesize that high-dose tamoxifen may be an effective modulator of doxorubicin in the treatment of HCC, and suggest that biochemical modulation of PKC as a measure to improve systemic chemotherapy for HCC deserves further investigation.
Subject(s)
Apoptosis/drug effects , Doxorubicin/pharmacology , Protein Kinase C/metabolism , Tamoxifen/pharmacology , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Hormonal/agonists , Antineoplastic Agents, Hormonal/pharmacology , Biological Transport, Active/drug effects , Doxorubicin/administration & dosage , Drug Resistance , Drug Synergism , Enzyme Activation/drug effects , Fluorescent Dyes , Humans , Isoenzymes/metabolism , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/enzymology , Rhodamine 123 , Rhodamines , Tamoxifen/administration & dosage , Tetradecanoylphorbol Acetate/pharmacology , Tumor Cells, Cultured , ras Proteins/metabolismABSTRACT
Systemic chemotherapy for advanced gastric cancer is frequently associated with significant treatment-related toxicity, which is particularly serve in patients presenting with a poor general condition. A search for effective and low-toxic regimens for this group of patients is mandatory. A weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) has previously been demonstrated to be an effective treatment for advanced colorectal cancer with minimal toxicity. In the past 3 years, this regimen has been tested at our institutes in patients with advanced gastric cancer, the general condition of whom had made the use of intensive combination chemotherapy impossible. The regimen consisted of a weekly 24-hour infusion of 2,600 mg/m2 of 5-FU and 300 mg/m2 of leucovorin. From August 1992 to December 1995, 34 patients had been treated with this regimen for a total of 488 courses (average: 14.4 per patient). Hematological toxicity of this regimen was minimal, with grade 3 or 4 leukopenia developing in only 1 (2.9%) patient. Other nonhematological toxicities were also negligible except a reversible neurotoxicity which developed in 2 patients. Twenty-five patients were eligible for response analysis. One complete response, 11 partial responses, 5 stable diseases, and 8 progressive diseases were observed. The response rate was 48% (32-72%, 95% CI). The median overall survival (OS) of the whole group was 7 months (range: 1-18+). The median OS and time to progression of the responders were 8.5 months (range: 2-18) and 5 months (range: 2-10+), respectively. The palliative effect was satisfactory with the Karnofsky performance status of the responders improving from a median of 50% (range: 20-90%) to 70% (range: 50-100%). Our retrospective data suggested that HDFL is an effective and low-toxic palliative treatment even in patients with a very poor general condition. We advocated that this regimen should be further tested in ordinary patients with advanced gastric cancer.
Subject(s)
Fluorouracil/administration & dosage , Leucovorin/administration & dosage , Stomach Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Male , Middle Aged , Survival AnalysisABSTRACT
Thymic carcinoma is known for its poor clinical outcome and unsatisfactory response to conventional chemotherapy. A 53-year-old woman was diagnosed as having metastatic thymic carcinoma in 1989. She received systemic chemotherapy containing cisplatin, doxorubicin, and cyclophosphamide, and involved-field radiotherapy. A durable complete remission was achieved and lasted for 4 years. When the disease recurred in 1995, she was found to have an autoimmune syndrome in addition to pleural effusion, a posterior mediastinal mass and a left adrenal mass. The autoimmune manifestations were seen as scleroderma, high titers of rheumatoid factor and anti-nuclear antibody. We adopted a novel HDFL regimen, which is composed of weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin, for this patient. Complete remission was achieved again, and autoimmune syndrome was well controlled.