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Background/aim: Glioblastoma is an incurable cancer with limited treatment options and a low survival rate. Temozolomide is the standard marketed small-molecule agent for glioblastoma therapy; therefore, we aimed to find new drugs among the marketed medicines for brain diseases because of their cerebral migratory property and found lomerizine, used for the treatment of migraine., Materials and Methods: We evaluated the effect of lomerizine and its metabolites against U251 glioblastoma cells and temozolomide-resistant cells, T98G and GB-1, caused by the expression of O(6)-methylguanine-DNA methyltransferase or P-glycoprotein, compared with temozolomide, and combined with it. The mechanism of action was investigated using inhibitors of necrosis or apoptosis., Results: Lomerizine and its metabolite (M6) inhibited the proliferation of glioblastoma cells with greater potency and efficacy than temozolomide, including against temozolomide-resistant cells. The effects of lomerizine and M6 on glioblastoma were mainly attributed to the inhibition of proliferation because cells were not rescued by cell death inhibitors, such as necrosis or apoptosis inhibitors, although they were slightly rescued by necrostatin-1. Additionally, lomerizine and M6 combined with temozolomide were more effective at inhibiting the proliferation of U251 and GB-1 cells at some doses than single treatments., Conclusion: Lomerizine has been used for migraine treatment because of its brain-penetrating properties without serious side-effects; thus, it might potentially be expected to be used alone for glioblastoma, including temozolomide-resistant glioblastoma, or in combination with temozolomide., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could enhance ICI efficacy in colon cancer using a syngeneic mouse model., Materials and Methods: The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed., Results: More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone., Conclusion: NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Fluoropyrimidine therapy or oxaliplatin combination therapy is recommended for patients with stage III colorectal cancer as adjuvant chemotherapy (AC). However, the criterion for selecting these regimens is still unclear in patients with stage III rectal cancer (RC). In order to select an appropriate regimen of AC for such patients, it is needed to identify characteristics associated with tumor recurrence., Patients and Methods: The records of 45 patients with stage III RC undergoing AC using tegafur-uracil/leucovorin (UFT/LV) were retrospectively reviewed. The cut-off value of characteristics was determined using a receiver operating characteristic curve for recurrence. Univariate analyses using Cox-Hazard model for predicting recurrence were performed with clinical characteristics. Survival analysis was performed using Kaplan-Meier method and log-rank test., Results: Thirty patients (66.7%) completed AC using UFT/LV. Fifteen patients (33.3%) did not complete AC because of adverse events, tumor recurrence and others. Sixteen patients (35.6%) had recurrence. Univariate analyses revealed that lymph node metastasis (N2/N1) (p=0.002) was associated with tumor recurrence. Survival analysis showed that lymph node metastasis (N2/N1) could stratify recurrence-free survival (p<0.001)., Conclusion: N2 lymph node metastasis can predict tumor recurrence in patients with stage III RC undergoing AC using UFT/LV., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Lenalidomide (LND) is an oral anticancer drug used to treat various malignant hematologic diseases, including multiple myeloma. The most common adverse events with LND are myelosuppression, thrombosis and pneumonia. Myelosuppression is reversible, and thrombosis can be treated with prophylactic administration of antithrombotic drugs. Pneumonia is less common and its incidence profile in clinical studies is unclear. This study aimed to evaluate the incidence and onset timing of LND-related lung toxicity and outcome details using the Japanese Adverse Drug Event Report (JADER) database., Patients and Methods: Adverse events with LND reported between April 2004 and March 2021 were selected. Data on lung adverse drug reactions (ADRs) were analyzed, and safety signals were estimated using reported odds ratios (RORs) and 95% confidence intervals (CIs). We also estimated the timing of onset of lung toxic signs., Results: A total of 10,929 ADRs were attributed to LND. Of these, 908 were lung toxicities. The most frequently reported ADRs with significantly high RORs were pneumonia (559 cases, ROR=3.89, 95% CI=3.57-4.24) and bacterial pneumonia (38 cases, ROR=2.02, 95% CI=1.46-2.78). Median onset of pneumonia and bacterial pneumonia were 84 and 74 days, respectively. Prognoses of patients who received LND and had pneumonia and bacterial pneumonia were poor, with 10-20% non-recovery and deaths., Conclusion: The findings indicate that pneumonia and bacterial pneumonia, among all LND-related lung toxicities, may be associated with immunosuppression, suggesting the importance of monitoring respiratory symptoms within the first 3 months of treatment., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Durvalumab is a human monoclonal antibody targeting programmed cell death ligand 1. It is classified as an immune checkpoint inhibitor and has shown high efficacy as maintenance therapy after chemoradiation for stage III non-small-cell lung cancer and as the primary treatment for small-cell carcinoma. Interstitial lung disease is the most common adverse event leading to durvalumab discontinuation. Hence, this study was aimed at assessing the incidence and timing of durvalumab-induced lung toxicity by using the Japanese Adverse Drug Event Report (JADER) database., Patients and Methods: Adverse Adverse events (AEs) of durvalumab reported from August 2018 to March 2021 were extracted. Data on lung AEs were analysed to estimate relative risk using reporting odds ratios (RORs) and 95% confidence interval (CIs). Furthermore, the times of onset of signs of lung toxicity were also estimated., Results: Overall, 2,162 AEs attributable to durvalumab were obtained. Of these, 1,239 were lung toxicities, the most common among which were pneumonia, interstitial lung disease, and radiation-associated pneumonitis. The corresponding RORs (95% CIs) for these signs were 271.50 (244.79-301.11), 5.96 (5.29-6.72), and 713.21 (595.04-854.85), respectively. The median (interquartile range) times of onset were 32.5 (28.5-35.5), 31.5 (28.5-41.5), and 28.5 (28.5-30.5) days, respectively., Conclusion: Among the AEs of durvalumab, pneumonia, interstitial lung disease, and radiation-induced pneumonitis were associated with high RORs, suggesting a strong causal relationship with durvalumab. Interstitial lung disease and radiation-induced pneumonitis most often occurred approximately 30 days after treatment initiation, suggesting that monitoring for adverse events during this period is important., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs., Patients and Methods: Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted., Results: We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively., Conclusion: Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Bendamustine-associated skin damage occurs frequently in Japan and can have a profound impact on health-related quality of life. To our knowledge, there are no reports on the timing of skin damage caused by bendamustine. This study assessed trends in and the time to onset of skin damage caused by bendamustine using the Japanese Adverse Drug Reaction Reporting Database (JADER)., Patients and Methods: Data related to skin damage with more than five reported cases from April 2004 to March 2021 were extracted from JADER, and the relative risk of adverse events was estimated using the reporting odds ratio and 95% confidence interval. The data were analyzed for time to onset of skin damage., Results: JADER included a total of 2,450 reports of adverse drug reactions from bendamustine. Of these, 170 skin ailments of 10 types were reported to be associated with bendamustine. Significant associations for skin damage were found for rash, herpes zoster, and infusion-related reactions. The reporting odds ratios (with 95% confidence interval) for rash, herpes zoster, and infusion-related reaction were 1.63 (1.19-2.21), 3.25 (2.20-4.78), and 7.25 (4.84-10.85), respectively. The median onset (interquartile range) of rash, herpes zoster, and infusion-related reactions caused by bendamustine were 13 (10-28), 60 (28-107), and 6 (1-28) days, respectively., Conclusion: A comprehensive study using a pharmacovigilance approach enabled us to identify that a rash or infusion-related reaction may be expected within 2 weeks of treatment with bendamustine and that the onset of herpes zoster occurs at a median of 2 months after treatment with bendamustine., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The efficacy and feasibility of gemcitabine plus cisplatin (GC) chemotherapy in an adjuvant setting is unclear in patients with biliary tract cancer (BTC) undergoing major hepatectomy., Patients and Methods: Patients with BTC who underwent major hepatectomy between 2008 and 2018 were included. Patients who received adjuvant chemotherapy (AC) were then divided into two groups: a GC group and a gemcitabine (GEM) alone group. AC-related factors and patient outcomes were investigated., Results: Fifty (GC: 28, GEM: 22) patients received AC, and 33 patients did not. No difference in completion rate, relative dose intensity, or adverse events was seen between the two AC groups. Multivariate analysis revealed that AC with GC was an independent predictor of improved survival and reduction of early recurrence., Conclusion: AC with GC is tolerable and associated with better outcomes in patients with BTC who have undergone major hepatectomy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Computed tomography and positron emission tomography cannot detect all minute distant metastases and fully evaluate extensive vascular invasion in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate predictors of laparotomy only and palliative surgery in PDAC patients planning surgical resection., Patients and Methods: We reviewed 239 PDAC patients planning surgical resection. Patients were divided into two groups based on resection status. Multivariate analyses were performed to identify predictors of unresectable disease at laparotomy., Results: Twenty-five patients had unresectable disease at laparotomy. Multivariate analysis revealed that anatomical borderline resectable status (yes/no) (HR=5.458, p=0.012), pretreatment CA19-9 (>260/≤260 ng/ml) (HR=4.907, p=0.041), and tumor size (>25/≤25 mm) (HR=21.42, p=0.004) were associated with unresectable disease at laparotomy., Conclusion: Borderline resectable status, pretreatment CA19-9, and tumor size were closely associated with unresectable disease at laparotomy in PDAC patients planning surgical resection., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: An association between the pathological response to neoadjuvant chemotherapy (NAC) and the efficacy of adjuvant chemotherapy (AC) in patients with pancreatic ductal adenocarcinoma (PDAC) remains unknown., Patients and Methods: A total of 121 patients with PDAC who underwent a pancreatectomy between January 2013 and March 2020 were divided into two groups: an upfront surgery (UFS) group (n=42), and an NAC (gemcitabine plus S-1) group (n=79). In the NAC group, the pathological response was evaluated using the Evans classification., Results: The overall survival was significantly higher in patients with an AC relative dose intensity (RDI) ≥80% than in patients with an AC RDI <80% in the UFS, NAC-Evans IIa, and NAC-Evans IIb+III groups. However, this difference was not observed in the NAC-Evans I group., Conclusion: AC is preferable for patients with NAC-Evans IIa or IIb+III, but more effective AC regimens may be needed for NAC-Evans I patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Colonic cancer is associated with a low incidence of peritoneal metastasis compared with gastric cancer; however, the reason for this remains unclear. In this study, a model of peritoneal dissemination using the CT26 murine colon cancer cell line was used to analyze the physiological roles of cancer-derived exosomes., Materials and Methods: Exosomes were collected from the supernatant of CT26 cell culture by ultracentrifugation. The number of peritoneal disseminations in two mouse models of colonic cancer pre-administered exosomes or phosphate-buffered saline were compared., Results: Cancer-derived exosomes suppressed peritoneal dissemination compared to phosphate-buffered saline. After administration of exosomes, the number of intraperitoneal macrophages and the expression of inducible nitric oxide synthase increased. Furthermore, cancer-derived exosomes increased activated natural killer cells and interferon-γ expression., Conclusion: Tumor-derived exosomes from colonic cancer may suppress peritoneal metastasis via an immunological mechanism., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: γδ T cells mediate cytotoxicity against prostate cancer (PCa) cells in vitro; however, the clinical efficacy of γδ T cell-targeted immunotherapy for recurrent and metastatic PCa is unsatisfactory. We hypothesized that the resistance of recurrent and metastatic PCa to γδ T cells is related to the presence of prostate cancer stem cells (PCSCs), and we examined their relationship., Materials and Methods: PCa spheres (prostaspheres) were generated from five PCa cell lines, and their susceptibility to cytotoxicity by γδ T cells was investigated. Expression of stemness-related markers was evaluated by qRT-PCR., Results: Prostasphere-derived cancer cells were resistant to lysis by γδ T cells and expressed higher levels of several stemness markers, including CD133, NANOG, SOX2, and OCT4, than the parental PCa cell lines., Conclusion: Ex vivo-expanded γδ T cells are not effective against PCSCs., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Few studies have studied micro hepatic vein invasion in hepatocellular carcinoma (HCC). We explored the correlation between hepatic vein invasion and hepatitis B/C virus infection., Patients and Methods: Between April 2000 and February 2018, 869 patients underwent liver resection for HCC at a single center. The patients were divided into two groups: those with micro hepatic vein invasion (VV+) and those without (VV-). The clinical data, overall survival (OS) and correlations with the presence of hepatitis B and C viruses were investigated., Results: There were 817 VV- patients and 43 VV+ patients. OS was 66.2 months for VV- patients and 9.9 months for VV+ patients (p=0.0010). VV+ patients had significantly higher levels of serum HBV DNA (p=0.016)., Conclusion: HCC patients with micro hepatic vein invasion showed significantly shorter OS. A higher level of HBV DNA appears to be a risk factor for micro hepatic vein invasion., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study aimed to obtain accurate differential diagnosis (DDx) of multicentric carcinogenesis (MC) and intrahepatic metastasis (IM) in recurrent lesions of hepatocellular carcinoma., Materials and Methods: A total of 79 patients who underwent re-hepatectomy (2000-2013) were examined. PCR was used to analyze 13 chromosomal microsatellite loci by PCR. On the basis of this genetic analysis, the recurrent lesions were diagnosed as IM, MC or not determined (ND). Subsequently, DDx was compared with types of resection and outcome., Results: The recurrent lesions were diagnosed as IM in 33 patients, MC in 44, and ND in 2. The anatomical resection group included 14 IM lesions (28%) and 36 MC lesions (72%), while the non-anatomical resection group included 19 IM lesions (70%) and 8 MC lesions (30%) (p<0.001)., Conclusion: Anatomical resection at initial hepatectomy may reduce the likelihood of IM recurrence, leading to a better outcome for patients with HCC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recently, several systemic inflammation-based scores, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), modified Glasgow prognostic score (GPS), and prognostic nutritional index (PNI), have been proposed as prognostic factors for several cancers. In this study, we aimed to determine the influence of systemic inflammation-based scores and nutrition status on the outcome in patients receiving chemotherapy for unresectable pancreatic cancer., Patients and Methods: A total of 93 consecutive patients who underwent chemotherapy for unresectable pancreatic cancer at Osaka Medical College Hospital, Takatsuki, Japan, between January 2008 and December 2014 were eligible for this study. The outcomes assessment included one- and two-year overall survival (OS) rates, according to changes in LMR and PNI prior to, and following chemotherapy., Results: LMR<3.4 (OR=5.02, 95%CI=1.559-19.85, p=0.005) and PNI<43 (OR=3.53, 95%CI=1.057-14.21, p=0.03) independently predicted a poor outcome in patients receiving chemotherapy for unresectable pancreatic cancer using multivariate analysis. According to changes in LMR and PNI prior to, and following chemotherapy, compared to patients who maintained LMR≥3.4, patients whose LMR decreased from ≥3.4 to <3.4 had significantly lower OS rates (p<0.001). Similarly, compared to patients who maintained PNI≥43, patients whose PNI deteriorated had significantly lower OS rates (56.2% versus 25.8% at one year, and 12.5% versus 0% at two years; p=0.003)., Conclusion: LMR<3.4 and PNI<43 are identified as independent predictors of poor outcome in patients receiving chemotherapy for unresectable pancreatic cancer. LMR and PNI may help clinicians identify patients at high risk for poor prognosis., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The inhibitory activities of docetaxel at a wide range of doses (0.1-10 mg/kg; subcutaneously (s.c.), once/week) in nude mice bearing a human prostate cancer cell (DU145), xenograft model with implantation of DU145 cells or a DU145 solid tumor were examined. This systematic trial demonstrated that (i) docetaxel was more effective in the xenograft model formed by implantation of DU145 cells than in the solid DU145 tumor; (ii) administration of 2.5 mg/kg docetaxel was the critical dose because inhibitory activities were not observed at 2.5 mg/kg, while they were noted at 5 mg/kg and 10 mg/kg in both implantation approaches; (iii) edema-like effects (plump body shape and legs) were observed in both groups at 2.5 mg/kg and the tumor sizes, often increased by blood plasma and other fluids, as well as body weights were higher than at other doses; and (iv) suppression of body weight gain was observed at 10 mg/kg docetaxel., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The newly-synthesized naftopidil analog HUHS1015 suppresses tumor growth and induces apoptosis of cells from a variety of cancer types. The present study was conduced to assess the effect of HUHS1015 on human colonic cancer cells and to clarify the underlying mechanism., Results: HUHS1015 reduced cell viability of Caco-2 and CW2 human colonic cancer cell lines in a concentration (0.3-100 mM)-dependent manner. HUHS1015 increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in both cell lines. In flow cytometry using propidium iodide and annexin V, HUHS1015 significantly increased the populations of cells undergoing primary necrosis, early apoptosis, and late apoptosis/secondary necrosis in both cell lines. In the cell-cycle analysis, HUHS1015 increased the proportion of the sub-G1 phase of cell, which corresponds to apoptotic cells. HUHS1015 perturbed the mitochondrial membrane potential and reduced the intracellular ATP level. HUHS1015 activated caspases 3, -4, -8, and -9, particularly caspase-3. HUHS1015 promoted cytochrome c release from the mitochondria. HUHS1015 significantly inhibited tumor growth in mice inoculated with CW2 cells., Conclusion: HUHS1015 induces necrosis by lowering the intracellular ATP level in association with mitochondrial damage and caspase-dependent apoptosis. This occurs in part by stimulating cytochrome c release from the mitochondria to activate caspase-9 followed by the effector caspase-3, responsible for suppression of colonic cancer proliferation in the mouse xenograft model., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The present study investigated the mechanism underlying the apoptosis of MKN28 human gastric cancer cells induced by the phosphatidylinositol (PI) derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidyl-D-1-inositol (diDCP-LA-D-PI) and its enantiomer diDCP-LA-L-PI., Materials and Methods: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, enzymatic caspase assay, real-time reverse transcription-polymerase chain reaction (RT-PCR), and western blotting were carried-out., Results: Both diDCP-LA-D-PI and diDCP-LA-L-PI induced caspase-independent apoptosis of MKN28 cells, with the potential for diDCP-LA-L-PI being much greater than that of diDCP-LA-D-PI. diDCP-LA-D-PI and diDCP-LA-L-PI accumulated apoptosis-inducing factor (AIF) and AIF-homologous mitochondrion-associated inducer of death (AMID) in the nucleus., Conclusion: diDCP-LA-D-PI and diDCP-LA-L-PI induce caspase-independent apoptosis of MKN28 cells by accumulating AIF and AMID in the nucleus, with different potentials., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: The epidermal growth factor family (EGF) has been suggested to influence the sensitivity to anti-epidermal growth factor receptor therapy. We examined the correlation between circulating levels of the epidermal growth factors amphiregulin and transforming growth factor-α (TGF-α) and the MET ligand hepatocyte growth factor and sensitivity to the anti-epidermal growth factor receptor antibody in colorectal cancer (CRC) patients., Materials and Methods: Plasma levels of each ligand were measured by enzyme-linked immunosorbent assay in 51 patients with wild-type KRAS CRC., Results: Patients with high hepatocyte growth factor (HGF) levels had a significantly lower disease control rate (DCR) and shorter median progression-free survival (PFS) and overall survival (OS) than those with low expression levels. Amphiregulin was correlated with objective response rate (ORR) but not with PFS or OS. Cetuximab response and survival were not associated with TGF-α., Conclusion: Circulating HGF may help identify CRC patients most likely to benefit from anti-epidermal growth factor receptor antibody therapy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Pemetrexed inhibits three key folate enzymes: thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The relationship between the clinical efficacy of pemetrexed and the expression of folate enzymes in lung cancer cells is unknown. The purpose of this study was to determine whether TYMS, DHFR, and GARFT expression affect the therapeutic efficacy of pemetrexed., Patients and Methods: Participants (n=50) were patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed. Samples were obtained by tumor biopsy before treatment. We isolated cancer cells from formalin-fixed paraffin-embedded tissues using laser microdissection, and mRNA levels were analyzed using real-time reverse transcription polymerase chain reaction. Protein expression was evaluated using immunohistochemistry. We assessed the association between TYMS, DHFR, and GARFT expression and the therapeutic efficacy of pemetrexed., Results: The median age was 66.8 years. Compared to healthy tissues, the relative TYMS mRNA expression ranged from 0.001 to 41.613 (mean 4.638 ± 1.357), and was significantly lower in responders compared to non-responders (1.671 ± 0.844 versus 5.978 ± 1.895, p=0.0142). Progression-free survival was prolonged in patients with lower TYMS mRNA expression compared to those with higher TYMS mRNA expression, but the difference was not statistically significant (18.0 versus 13.3 weeks, p=0.3001). DHFR and GARFT mRNA expression did not correlate with the efficacy of pemetrexed., Conclusion: We specifically analyzed TYMS, DHFR, and GARFT mRNA expression levels in lung cancer cells from biopsy specimens using laser microdissection. TYMS mRNA expression affected the therapeutic efficacy of pemetrexed and could therefore constitute a useful predictive biomarker for NSCLC patients receiving pemetrexed.

Background: Previous studies showed the prognostic impact of inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP), in resected non-small cell lung cancer (NSCLC). However, there are no studies that examined both of these markers simultaneously., Patients and Methods: Three hundred and one consecutive cases of resected NSCLC with a follow-up period of more than 5 years were reviewed retrospectively., Results: A significant association was only observed between NLR and patients' survival (p<0.0001). High CRP also led to a higher 5-year survival rate than low CRP (38.71% vs. 70.71%, p<0.0001). We evaluated the prognostic significance of the use of NLR and CRP combined. The 5-year survival of patients with both low NLR and low CRP was 74.18%. On the other hand, that of patients with both of these at a low level was significantly poor (20.00%, p<0.0001). Univariate and multivariate analyses of the clinicopathological factors affecting survival revealed that the combined use of preoperative NLR and CRP was an independent prognostic determinant., Conclusion: The combined use of preoperative NLR and CRP might be useful to predict the prognosis of patients with NSCLC.

Background: The prognostic impact of neutrophil to lymphocyte ratio (NLR) in non-small cell lung cancer (NSCLC) was examined using patients with a follow-up period more than 5 years., Patients and Methods: Two hundred and eighty four consecutive resected NSCLC patients were reviewed retrospectively. In this study, patients who were treated with a follow-up period less than 5 years were omitted,, Results: The mean value of NLR was 2.44±2.22 (range: 0.56-29.44). The 5-year survival of the patients with a high NLR (≥2.5) was significantly worse than that of the patients with a low NLR (47.06% vs. 67.84%, p<0.0001). Univariate analysis of the clinicopathological factors affecting survival revealed that age, gender, histology, pT status, pN status, high serum CEA level, positive findings of pleural lavage cytology and high NLR were significant risk factors for reduced survival. On multivariate analysis, a high NLR was an independent risk factor for reduced survival., Conclusion: A high preoperative NLR may be a convenient biomarker to identify patients with a poor prognosis after resection for NSCLC.

Background: The aim of this study was to evaluate the activity and toxicity of epirubicin and cyclophosphamide followed by weekly paclitaxel with or without trastuzumab as primary systemic therapy in locally advanced breast cancer., Patients and Methods: Patients with T2-4 (>3 cm) or N1-3 breast cancer received epirubicin (100 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every three weeks for four cycles followed by paclitaxel (80 mg/m(2)) every week for twelve cycles. Trastuzumab (initially 4 mg/kg, then 2 mg/kg) was added to paclitaxel in HER2-positive patients. The primary endpoint was the pathological complete response (pCR) rate in the breast and axilla, and secondary endpoints were the breast-conserving rate and toxicity., Results: Forty-three patients were enrolled into this study and 3 patients withdrew. The pCR rate was 20.0% (95% confidence interval, 10.5-34.8%). Patients with HER2-positive tumours had a significantly higher pCR rate than the others (62.5% vs. 9.4%; p=0.0008). Twenty-four patients (60.0%) underwent breast-conserving surgery. Grade 4 neutropenia was recorded in 30.0% of the patients, and febrile neutropenia occurred in 7 patients (17.5%)., Conclusion: Epirubicin and cyclophosphamide followed by weekly paclitaxel, either with or without trastuzumab, was an active and well-tolerated treatment for locally advanced breast cancer.

Background: Prognostic impact of tumour marker index (TMI) based on preoperative serum carcinoembryonic antigen (CEA) and CYFRA 21-1 in non-small cell lung cancer (NSCLC) was examined using patients with a follow-up period more than 5 years., Patients and Methods: Two hundred and ninety-three consecutive NSCLC patients were reviewed retrospectively, and any patients with follow-up periods less than 5 years were omitted., Results: The 5-year survival of the patients with normal and high serum CEA levels was 71.52% and 48.41%, respectively (p<0.0001). The 5-year survival of the patients with a high serum CYFRA 21-1 level was 39.66%, which was significantly poorer compared with that of the patients with a normal serum CYFRA 21-1 level (66.95%, p<0.0001). There was a 5-year-survival rate of 72.28% in patients with a TMI less than or equal to 1.0 compared to only 37.08% in patients with a TMI greater than 1.0 (p<0.0001). Both univariate and multivariate analyses indicated the independent prognostic impact of TMI., Conclusions: TMI may be useful for predicting the prognosis of NSCLC patients.

A 75-year old woman presented with diffuse left breast enlargement, redness, edema, and a firm palpable lymph node with skin fixation in the left axilla. The tumor was diagnosed as invasive ductal carcinoma with a strongly positive human epidermal growth factor receptor 2 (HER2) score (3+). She was diagnosed as having inflammatory breast cancer (IBC) (T4d N2M0, stage IIIb). The patient received primary systemic chemotherapy with 4 courses of epirubicin 75 mg/m(2) and cyclophosphamide 500 mg/m(2) every three weeks, then 12 courses of paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (initially 4 mg/kg) weekly. Six months after the start of chemotherapy, a left modified radical mastectomy with axillary dissection was performed. No cancer cells in the breast specimen and no metastases to the axillary nodes were observed, so the therapeutic effect was determined as a pathological complete response (pCR). This report suggests that combination therapy with epirubicin and cyclophosphamide followed by trastuzumab and paclitaxel was useful for HER2-positive IBC.

Background: Previous studies have reported any prognostic impact of preoperative leukocytosis, anemia and thrombocytosis in non-small cell lung cancer (NSCLC). The significance of the combined use of these 3 abnormal blood cell counts was investigated., Patients and Methods: Two hundred and eighty-nine consecutive NSCLC patients were reviewed retrospectively., Results: The patients with leukocytosis, anemia and thrombocytosis had significantly worse prognosis. The 5-year survival of the patients with all three of these abnormal blood cell counts was 25.0%, which was significantly poorer compared with that of the patients without any of these abnormal cell counts (78.23%). The 5-year survival of the patients with 1 or 2 out of the three abnormal blood cell counts was an intermediate value. Both univariate and multivariate analyses indicated the independent prognostic impact of the use of these three abnormal blood cell counts combined., Conclusion: The use of leukocytosis, anemia and thrombocytosis combined might be useful for predicting the prognosis of NSCLC patients.

Background: The aim of this study was to evaluate the activity and toxicity of epirubicin and cyclophosphamide (EC) followed by docetaxel as primary systemic chemotherapy (PST) in locally advanced breast cancer., Patients and Methods: In this phase II trial, 46 patients with locally advanced breast cancer (T > 3 cm or N > 1) received epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles, followed by docetaxel (70 mg/m2) every 3 weeks for four cycles. Primary endpoints were pathological and objective response in the breast and axilla, and toxicities., Results: The clinical response rate was 80.4% (95% confidence interval, 68.9-91.9%). Pathological response evaluation revealed 6 complete responses (CR: 13.0%). Patients with ER-negative tumors had a significantly higher rate of pathological CR than the others (33.3% vs. 3.2%; p = 0.0105). Febrile neutropenia occurred in 4 patients (8.7%)., Conclusion: EC followed by docetaxel is an active and well-tolerated treatment as PST for locally advanced breast cancer.

Background: Only a few studies have reported any prognostic impact of the preoperative hemoglobin level itself in resectable non-small cell lung cancer (NSCLC). The survival impact of preoperative hemoglobin level and the relationship between hemoglobin and serum CEA level were investigated., Patients and Methods: Two hundred and forty consecutive NSCLC patients were reviewed retrospectively., Results: The 5-year survival of patients with low and those with a normal hemoglobin level was 42.99% and 73.47%, respectively. Both univariate and multivariate analyses indicated the independent prognostic impact of the hemoglobin level. The result for stage I patients was identical. Patients with normal hemoglobin could be subdivided into 2 groups based on their serum CEA level; the 5-year survival of patients with normal and those with elevated CEA was 81.72% and 57.24%, respectively., Conclusion: The preoperative hemoglobin level was a prognostic factor for NSCLC patients. The combined use of hemoglobin and CEA levels might be useful to predict the prognosis of patients.

The platinum-based drug cisplatin (cis-diamminedichloroplatinum (II)) is widely used in cancer therapy. However, cancer cells can develop resistance after exposure to cisplatin. Recently, many studies have pointed to the involvement of plasma membrane ion channels in a cell's response to cisplatin. Our group has found that pretreatment with cisplatin enhanced the activity of volume-sensitive C-channels in human epidermoid cancer KB cells; cisplatin-resistant KCP-4 cells derived from KB cells, on the other hand, lacked functional expression of these channels. This suggests that the activity of volume-sensitive Cl(-) channels is an important factor in determining the sensitivity of cancer cells to cisplatin. Furthermore, when volume-sensitive Cl(-) channel function was partially restored in cisplatin-resistant KCP-4 cells treated with a histone deacetylase inhibitor, KCP-4 cells exhibited a restoration of sensitivity to cisplatin; this increased sensitivity was inhibited by a volume-sensitive Cl(-) channel blocker. We therefore propose that impaired activity of the volume-sensitive Cl(-) channel is involved in the acquired cisplatin resistance of these cancer cells. In this review, we will outline the relationship between volume-sensitive Cl(-) channels, cisplatin-induced apoptosis, and cisplatin resistance. Activating the volume-sensitive outwardly-rectifying Cl(-) channel may be a new strategy in treating clinical cisplatin resistance.

Background: The primary objective of this study was to determine the maximum tolerated dose (MTD), the toxicity profile and the recommended dose (RD) for phase II of a combination of S-1 and weekly administration of docetaxel., Patients and Methods: Patients with histologically diagnosed recurrent or unresectable locally advanced gastric cancer were enrolled. A fixed oral dose of 80 mg/m2 S-1 was given for 3 weeks. Docetaxel was infused intravenously on day 1, 8 and 15, repeated every 5 weeks. A pharmacokinetic study was also performed., Results: A total of 14 patients were enrolled. One dose-limiting toxicity (DLT) (grade 3 diarrhea with febrile neutropenia) occurred at level 2. DLTs occurred in 3/5 patients at level 3, (grade 3 stomatitis, with febrile neutropenia or continuous grade 4 neutropenia). The pharmacokinetic study suggested no drug interactions. Overall response and disease control rates were 20% and 80%, respectively. The response rate at the RD (level 2) was 50%. Overall survival was 9.4 months., Conclusion: RD was level 2 (80 mg/m2 of S-1 for 3 weeks and 20 mg/m2 of docetaxel on day 1, 8 and 15, every 5 weeks). Dose intensities of S-1 and docetaxel were 48 mg/m2/week and 12 mg/m2/week, respectively. This regimen showed promising activity for advanced gastric cancer.

Background: Controversy exists regarding the relationship between serum carcinoembryonic antigen (CEA) level and T status in non-small cell lung cancer., Materials and Methods: Two hundred and forty-seven lung cancer patients with pN0 disease were included in the study and the relationship between serum CEA level and T status, tumor size and degree of local extension was investigated., Results: Patients with tumors 0 to 1.5 cm in diameter had significantly low serum CEA level. However, there were no significant differences in serum CEA level among other tumor size groups. Serum CEA level was not related to the degree of local extension. The 5-year survival of patients with both normal serum CEA levels and T1 disease was significantly better than that of patients with high serum CEA level and 72-4 disease., Conclusion: Serum CEA levels do not always relate to T status. The combined use of these factors might be useful in predicting the prognosis of pN0 non-small cell lung cancer patients.

Background: The difficulty encountered in hepatectomy for the removal of a malignant tumor in the hepatic caudate lobe has recently been reported. However, few reports have described the clinical features of hepatic caudate lobe metastases from colorectal carcinoma., Patients and Methods: Retrospective clinicopathological data for 13 consecutive patients with colorectal metastases to the hepatic caudate lobe were analyzed for their various clinical aspects and long-term outcomes., Results: The tumor-free margin of the resected specimen was significantly smaller in the hepatic caudate lobe metastases group than in the other 178 patients with colorectal metastases in other sites of the liver (p<0.01), while the invasiveness of hepatectomy, as judged by the volume of liver resected and the duration of the procedure, was higher in the hepatic caudate lobe metastases group. Hepatic disease-free survival rates in the caudate lobe metastases group were lower than in the other group (p<0.01). By multivariate analysis, metastases to the hepatic caudate lobe negatively impacted hepatic disease-free survival (adjusted relative risk, 2.085; p=0.048)., Conclusion: In patients with hepatic caudate lobe metastases, hepatectomy with clear surgical margins is difficult, even when major hepatectomy is attempted. Hepatic metastasis in the caudate lobe is a risk factor for early liver recurrence after hepatectomy.

Bone morphogenetic protein (BMP), which is a member of the transforming growth factor beta (TGF-beta) superfamily, has powerful osteoinductive effects and various biological activities in a variety of cells. The effect of BMP-2 on the human carcinoma cell line TSU-Pr1 was examined. BMP-2 was found to inhibit the migration and invasiveness, but not the proliferation, of TSU-Pr1 cells. Gel zymography for matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) detection revealed that BMP-2 down-regulated the activity of MMP-9, but not of MMP-2 or uPA. BMP-2 also reduced the secretion of MMP-9 into the culture media, but did not affect the secretion of MMP-2, Timp-1, Timp-2 or Timp-3. These results suggest that BMP-2 inhibits migration and decreases MMP-9 secretion to suppress the invasiveness of TSU-Pr1 cells. This is the first report of a role for BMP signaling in reducing the invasiveness of cancer cells.

Background: The purpose of this study was to evaluate the activity and toxicity of epirubicin plus docetaxel as neoadjuvant chemotherapy for locally advanced breast cancer., Patients and Methods: In this single-center, phase II trial, twenty-one patients with locally advanced breast cancer (T>3 cm or N>1) received epirubicin (70 mg/m2) and docetaxel (60 mg/m2) on Day 1 of each cycle for up to 6 cycles., Results: Clinically complete responses (CR) were observed in 5 patients and partial responses were observed in 14 patients. The clinical response rate was 90.5% (95% confidence interval, 78.0-99.9). Eleven patients (52.4%) underwent breast conserving surgery. Pathological response evaluation revealed 2 CR (9.5%). Grade 4 neutropenia was recorded in 81.0% of the patients and febrile neutropenia occurred in 1 patient., Conclusion: The combination of epirubicin plus docetaxel was an active and well-tolerated treatment for locally-advanced breast cancer.

Background: Although the prognostic significance of the serum carcinoembryonic antigen (CEA) level in non-small cell lung cancer has been reported in several studies, it is unknown whether the serum CEA level is a prognostic determinant for pN1 disease or not., Materials and Methods: Seventy patients with pN1 non-small cell lung cancer who received complete resection were reviewed. The preoperative serum CEA level was measured in all patients., Results: The pN1 patients with pT2-4 disease, hilar node involvement, multiple N1 station and elevated serum CEA level (>5 ng/mL) had a significantly unfavorable prognosis. Although a serum CEA level higher than 5 ng/mL was not an independent prognostic determinant, more than 10 ng/mL was an independent factor by multivariate analysis. In patients with pT1-2N1 disease, a serum CEA level more than 10 ng/mL was also a prognostic determinant., Conclusion: An elevated serum CEA level, especially higher than 10 ng/mL, is a significant prognostic determinant for pN1 lung cancer patients.

Background: A highly specific antibody against recombinant human dihydropyrimidine dehydrogenase (DPD) has been developed to immunohistochemically assess DPD expression in tumors. A new oral DPD inhibitory fluoropyrimidine (DIF), S-1, is reportedly effective against gastric scirrhous carcinoma., Patients and Methods: In this study, the relationship between immunoreactivity to DPD in biopsy specimens and the effects of chemotherapy were investigated in 61 patients treated with first-line fluoropyrimidine-based chemotherapy (S-1:DIF, 5-FU:non-DIF) for gastric scirrhous carcinoma., Results: The response rate was significantly higher in patients with DPD-positive tumors than in those with DPD-negative tumors in the S-1 group (45.5%, 10.0%: p < 0.05), as compared to the 5-FU group (0%, 5.6%: p = 0.398). According to the median survival time, there was no significant difference between patients with DPD-positive tumors (364 days) and those with DPD-negative tumors (406 days; p = 0.626) in either the S-1 group or the 5-FU group (181 days and 256 days, respectively; p = 0.543)., Conclusion: This study indicates that S-1 may be effective even in gastric scirrhous carcinoma with a high level of DPD activity.

Twist, a transcription factor of the basic helix-loop-helix class, has been suggested to have oncogenic properties. We reported Twist expression was regulated by Wnt/beta-catenin signaling and that both Wnt-1 and Twist could contribute to mammary tumorigenesis. The aim of this study was to demonstrate the expression of Twist, Wnt-1 and Wnt-2 in human breast cancer tissue. We examined the expression in patients with breast cancer by RT-PCR and immunohistochemistry. RT-PCR of twenty-three pairs of cancer and normal breast tissue revealed that Twist was up-regulated in 69.6% (16/23) of the cancer lesions and 21.7% (5/23) of the normal breast tissues. Wnt-2 was up-regulated in all of the cancer lesions and 13.0% (3/23) of the normal breast tissues, whereas Wnt-1 was expressed in both the cancer and normal breast tissues of the five cases examined. Immunohistochemical analyses revealed that Twist was positively expressed in 52.2% (12/23) of the cancer lesions and 34.8% (8/23) of the normal breast tissues. Twist and Wnt-2 are highly expressed in breast cancer tissue, suggesting that both molecules could play important roles in mammary carcinogenesis.

Cyclooxygenase-2 (COX-2) is reported to play an important role in carcinogenesis. We examined COX-2 expression in patients with breast cancer and benign breast tumors. Immunohistochemical staining revealed a high level of COX-2 expression in malignant lesions of invasive ductal carcinoma (IDC) at a rate of 40% and a low level of expression in 15% of adjacent normal-appearing breast epithelia. Similarly, in ductal carcinoma in situ (DCIS), a high level of COX-2 expression was found in 80% of malignant lesions and a low level of expression in 50% of normal epithelia. Reverse transcriptional polymerase chain reaction (RT-PCR) performed in 7 of these cases disclosed that COX-2 expression was restricted to the malignant lesion. Further, all 10 cases of fibroadenoma and 10 cases of intraductal papilloma, both of which are benign tumors, had a high level of COX-2 expression. When overexpression of COX-2 was analyzed in relation to the clinicopathological features of the patients, no characteristic correlation was noted. Our results demonstrated that COX-2 is expressed in mammary tissue during tumorigenesis of the breast gland, suggesting that the cyclooxygenase isoenzyme may be a target for the prevention and treatment of breast cancer.

In a previous study, we found that TPA-mediated up-regulation of p21(WAF1/CIP1) induces growth arrest and differentiation of the human prostate cancer cell line TSU-Pr1. We investigated the effect of 12-O-tetra-decanoylphorbol-13-acetate (TPA) on growth and p21(WAF1/CIP1) protein levels in four prostate cancer cell lines. TPA treatment suppressed proliferation of the androgen-insensitive prostate cancer cell lines DU145 and PC-3. DU145 and PC-3 cells, however, showed neither morphological changes nor differentiation after TPA treatment. In contrast, TPA induced apoptosis of the androgen-sensitive prostate cancer cell line LNCaP. TPA induced up-regulation of p21(WAF1/CIP1) protein levels in all four cancer cell lines and this up-regulation was regulated by PKC in all four, but MAP kinase was associated with regulation only in TSU-Pr1 cells. Moreover, transient transfection with Adv-p21 resulted in growth arrest of all four cell lines. These data suggest that increased p21(WAF1/CIP1) production directly suppresses proliferation of prostate cancer cells regardless of androgen sensitivity. The pathway of TPA-induced increases in p21(WAF1/CIP1) levels was regulated by PKC. We thus conclude that p21(WAF1/CIP1) is a good candidate for use in treatment of prostate cancers because it suppresses proliferation of several prostate cancer cell lines.

We are interested in the possibility of new prostate cancer therapy that would control tumor malignancy via the induction of terminal cell differentiation. We have previously reported that staurosporine induced remarkable inhibition of cell proliferation and neuronal differentiation in human prostatic cancer TSU-Pr1 cells. In the present study, we investigated the alteration of cyclin-dependent kinase (CDK) activities and cell cycle in differentiated TSU-Pr1 cells. Treatment of TSU-Pr1 cells with staurosporine resulted in G1 arrest and suppression of CDK2 activity. Protein levels of CDK2 were essentially unchanged during this time. p21 protein, however, rapidly increased for 6 hours after treatment with staurosporine. p27 protein also increased gradually for 12 to 72 hours after treatment. CDK2-bound p21 and CDK2-bound p27 also increased. These results suggest that an increase in p21 and p27 protein causes increased binding with CDK2 and inhibition of CDK2 activity. We propose that the complex regulation of CDK2 plays a key role in G1 arrest of TSU-Pr1 cells after treatment with staurosporine.

Telomerase, the enzyme that synthesizes telomeric DNA, is repressed in normal human somatic cells but is activated with in vitro immortalization or during tumorigenesis. In this study, we investigated telomerase activity and expression of genes involved in telomerase activity in human myeloblastic leukemia ML-1 cells, differentiated synergistically by treatment with all-trans retinoic acid (ATRA) and granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF alone was not effective in changing telomerase activity whilst ATRA alone slightly decreased the activity. A combination of ATRA and GM-CSF remarkably reduced telomerase activity. We also detected remarkable suppression of hTERT mRNA expression in ML-1 cells treated with ATRA and GM-CSF. These results indicate that a synergistic down-regulation of telomerase activity and hTERT mRNA expression is induced by treatment with ATRA and GM-CSF in ML-1 cells.

We are interested in the possibility of new prostate cancer therapy that would control tumor malignancy via the induction of terminal cell differentiation. Here, we investigated the combined effect of various cAMP reagents on LNCaP human prostate carcinoma cells. Papaverine and prostaglandin E2 (PGE2), combined synergistically induced morphological changes. Electron microscope study suggested that cells treated with both reagents become like neuroendocrine cells. We then investigated the effect of both reagents on proliferation and malignancy of LNCaP cells. The malignancy of cells was analyzed by soft agar colony-forming assay and an in vitro invasion assay. Proliferation and malignancy of LNCaP cells treated with both reagents were significantly decreased in comparison to the proliferation and malignancy of untreated cells. Furthermore, the expression of oncogenes such as c-myc and Bcl-2 was suppressed in differentiated LNCaP cells. These results suggest that papaverine combined with PGE2 can synergistically induce neuronal differentiation as well as decrease the malignancy of human prostatic cancer LNCaP cells.

The combination of cyclophosphamide (CPA) and 5-fluorouracil (5-FU) is currently regarded as the most effective therapy for the treatment of patients with advanced and recurrent breast cancer. We evaluated the augmentation of antitumor activity and toxicity by coadministration of CPA and UFT (1M tegafur--4M uracil) instead of intravenous 5-FU on H-31 human breast cancer xenografts in nude mice. The maximum tolerable dose (MTD) of UFT alone (24 mg/kg) and CPA alone (85 mg/kg) had a significant effect on H-31 tumors in mice with 86.6% and 83.0% inhibition rates of tumor growth, respectively, and without loss of body weight, diarrhea or myelosuppression. The combined administration with full and 83.3% MTD of UFT and CPA augmented the antitumor activity compared to that of UFT alone and CPA alone. The relative tumor volume of the UFT plus CPA-treated group to the UFT- and CPA-treated groups was 0.28 and 0.36 for the full MTD, and 0.51 and 0.67 for 83.3% MTD, respectively. When CPA was consecutively administered to the tumor-bearing mice for 14 days, there were no decreases in the activities of enzymes related to 5-FU metabolism, but there was an significant increase in the activity of ribonucleotide reductase, suggesting that anabolism of 5-FU derived from tegafur is accelerated to some extent by coadministration of CPA. In conclusion, these results suggest that combination therapy with oral UFT and CPA may be useful for the long-term treatment of cancer patients with advanced and recurrent breast cancers.