Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin’s lymphoma

To prevent acute renal failure in children at risk for developing tumor lysis syndrome due to acute lymphoblastic leukemia or non-Hodgkin’s lymphoma treated according to international BFM protocols, we investigated recombinant urate oxidase (rasburicase) in the first Central European openlabeled, prospective, multicenter phase IV trial. Rasburicase was administered intravenously, at 0.2 mg/kg for 5 consecutive days to 36 patients. Blood levels of uric acid, creatinine, phosphorus, calcium, lactate dehydrogenase and complete blood count were measured daily during rasburicase treatment and on days 6, 7 and 12. Initial uric acid level decreased significantly by 4 hours (from 343 μmol/L to 58 μmol/L, p<0.001), except for one steroid-resistant patient who required hemodialysis on day 14 after having introduced combined cytostatic treatment. Comparing the data of a subgroup of 12 patients receiving rasburicase with that of a historic cohort of 14 patients treated with allopurinol indicated the superiority of rasburicase over allopurinol in prophylaxis and treatment of hyperuricemia in children with leukemia and lymphoma. Both authors contributed equally to this work. The study of the investigational new drug was approved and it was provided by Sanofi-Synthelabo Inc., Budapest, Hungary. This work was supported by the grant of the Health Science Council of the Ministry of Health, Republic of Hungary (ETT) No. 225.     

Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU)

PURPOSE: Although the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorouracil (FU), and 5-fluorouridine (FUrd). We assessed plasma concentrations of FdCyd and metabolites in patients receiving FdCyd and THU. METHODS: We validated an LC-MS/MS assay, developed for a preclinical study, to quantitate FdCyd and metabolites in human plasma. Patients were treated with five daily, 3-h infusions of FdCyd at doses of 5-80 mg/m(2) with 350 mg/m(2) THU. Plasma was obtained during, and before the end of infusions on days 1 and 5. RESULTS: The lower limits of quantitation for FU, FdUrd, FUrd, FC and FdCyd were 1, 1.5, 10, 3, and 10 ng/ml, respectively. Plasma FdCyd increased with dose, from 19-96 ng/ml at 5 mg/m(2) to 1,600-1,728 ng/ml at 80 mg/m(2). FdUrd was undetectable in patients treated with FdCyd doses <20 mg/m(2), and increased from 2.3 ng/ml at 20 mg/m(2) to 3.5-5.7 ng/ml at 80 mg/m(2). FU increased from 1.2-5.5 ng/ml at 5 mg/m(2) to 6.0-12 ng/ml at 80 mg/m(2). CONCLUSIONS: By co-administering FdCyd with THU, FdCyd plasma concentrations were achieved that are known to inhibit DNA methylation in vitro. The accompanying plasma FU and FdUrd concentrations are <10% those observed after therapeutic infusions of FU or FdUrd, while FdCyd levels are well above those required to inhibit methylation in vitro. Therefore, inhibition of DNA methylation with FdCyd and THU appears feasible.     

Antibody–cytotoxic drug conjugates in clinical trials and future perspectives: the development of Trojan horses

Chemotherapy and targeted agents, such as small molecules and monoclonal antibodies, have individually improved cancer medical therapeutics, yet there is still an unmet need for resistant or refractory disease. Drug combinations are usually more effective, but dose-limiting toxicities are of concern. The idea of developing a “smart bomb” treatment dates many years back. Nowadays, the development of biotechnology and the deeper knowledge of molecular biology have made possible the engineering of tumor-specific antibodies bearing cytotoxins directly and solely targeting the tumor cell, thus minimizing toxicity and increasing efficacy. Approved agents include trastuzumab emtansine (T-DM1) for breast cancer, brentuximab vedotin for Hodgkins’ disease, and gemtuzumab ozogamacin for relapsed acute myeloid leukemia. The present short review presents several newer antibody–drug conjugates (ADCs) in clinical studies and discusses ways to optimize ADC future design.     

Expression of Lewis y antigen and integrin αv, β3 in ovarian cancer and their relationship with chemotherapeutic drug resistance

Objective

This study investigates the expression of Lewis y antigen, integrin αv, β3 in epithelial ovarian cancer tissues. We further evaluate the relationship between their expression and chemotherapy resistance of ovarian cancer and its possible clinical significance.

Methods

Tissues of 92 patients with ovarian cancer meeting the inclusion criteria with complete follow-up data were enrolled and divided into chemotherapy resistant group and sensitive group. The expression and relationship of Lewis y antigen and integrin αv, β3 are assessed in paraffin sections using immunohistochemistry and double-labeling immunofluorescence method. Multivariate logistic regression analysis was used to investigate the relationship between age, clinical stage, differentiation, histologic subtype, Lewis y antigen and integrin αv, β3 expression in ovarian cancer patients.

Results

The expression rates of Lewis y antigen and integrin αv in the resistant group, significantly higher than the rates found in the sensitive group (p <0.05). Multivariate analysis showed that the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage were independent, drug resistance-related risk factors. The expression levels of Lewis y antigen and integrin αv, β3 were positively correlated with each other.

Conclusions

A close correlation between Lewis y antigen, integrin αv, β3 and ovarian cancer was observed. Lewis y antigen can influence the biological behavior of a tumor cell as an important composition of integrin αv, β3 by some signal pathway. And the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage are both independent, drug resistance-related risk factors.     

What is the Future for the Asian Pacific Journal of Cancer Prevention (and Control) and the Asian Pacific Organization for Cancer Prevention (and Control)?

The Asian Pacific Organization for Cancer Prevention was launched approximately 10 years ago withpublication of a booklet entitled ‘Introduction to Cancer Prevention in Tables and Figures’. This was followedby regular quarterly publication of the APJCP starting in the year 2000 - a new project for a new millenium -and a number of research meetings held across Asia. The journal is now in its 10th year, indexed on PubMed andScience Citation Index (Expanded) and relatively well known (not least for its yellow cover). However, its futureafter its tenth birthday remains uncertain, as there is no infrastructure in place to ensure continuation afterretirement of the present Chief/Managing Editor. The question of what might be the best way forward is thefocus for the present ‘Editorial Comment’. For financial as well as ecological reasons the APJCP is now anelectronic journal, printing and postage for issues of almost 200 pages being beyond the resources available.While the costs are therefore relatively low and primarily limited to staff salaries, they do need to be coveredand it cannot be simply assumed that the present support provided by the UICC Japanese National Committeewill continue long-term. Therefore comments and suggestions are invited from all interested individuals andinstitutions as to how the APJCP, and by extension the APOCP, should be organized and financed. Allcommunications received will be given space in the next few issues of the APJCP so that discussion can befostered and informed decisions made at the 5th APOCP General Assembly Conference in Istanbul, April 2010.     

Antitumor activity of human γδ T cells transducted with CD8 and with T-cell receptors of tumor-specific cytotoxic T lymphocytes

The difficulty in the induction and preparation of a large number of autologous tumor-specific cytotoxic T lymphocytes (CTL) from individual patients is one of major problems in their application to adoptive immunotherapy. The present study tried to establish the useful antitumor effectors by using γδ T cells through tumor-specific TCRαβ genes transduction, and evaluated the efficacy of their adoptive transfer in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice model. The TCRαβ gene was cloned from the HLA-B15-restricted CTL clone specific of the Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). The cloned TCRαβ as well as the CD8 gene were transduced into γδ T cells induced from peripheral blood lymphocytes (PBL). Cytotoxic T lymphocyte activity was examined using a standard 4 h (51) Cr release assay. Mice with a xenotransplanted tumor were treated with an injection of effector cells. Successful transduction of TCRαβ was confirmed by the staining of KK-LC-1-specific tetramers. The γδ T cells transduced with TCRαβ and CD8 showed CTL activity against the KK-LC-1-positive lung cancer cell line in a HLA B15-restricted manner. Adoptive transfer of the effector cells in a mice model resulted in marked growth suppression of KK-LC-1- and HLA-B15-positive xenotransplanted tumors. Co-transducing TCRαβ and CD8 into γδ T cells yielded the same antigen-specific activity as an original CTL in vitro and in vivo. The TCRαβ gene transduction into γδ T cells is a promising strategy for developing new adoptive immunotherapy.     

Comparison of photodynamic therapy for skin cancers and pre-cancers with δ-aminolevulinic acid

Objective  

The aim of the study was to compare the effects of photodynamic therapy (PDT) with δ-aminolevulinic acid (ALA) for patients with different kinds of skin cancers and pre-cancers.     

The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug–drug interactions

Purpose

Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed.

Method

Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors.

Results

Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28.

Conclusions

Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co-administered with substrates of UGT1A1.     

Does endoscopic follow-up improve the outcome of patients with benign gastric ulcers and gastric cancer?

This study investigated whether an endoscopic surveillance program for patients with "benign" gastric ulcers and gastric cancer leads to early detection of neoplasms and improves survival. The clinical course of all patients diagnosed between 1977 and 1986 as having either gastric ulcers or gastric cancer was followed for a minimum of 3 years. Of 597 patients with initially benign gastric ulcers, 452 (76%) returned for the recommended endoscopic follow-up examinations. In eight patients (1.8%), repeated biopsies disclosed malignant neoplasms; four of these patients (0.9%) had become asymptomatic. Survival curves were nearly identical in patients who complied and those who did not. Of 241 patients with gastric cancer, 72 underwent partial gastric resection with curative intent and survived the first year. Resectable cancer was detected in 5 of 48 patients who complied (10%); none of these patients died of cancer. However, 5-year actuarial survival rates were similar between the patients who complied and those who did not. Although endoscopic surveillance may detect resectable cancer in selected patients, it remains to be shown that such a strategy improves survival.     

Correlation of toxicity and efficacy with pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) (Caelyx®)

Purpose

Pegylated liposomal doxorubicin (PLD) is used to treat patients with breast and gynecological cancers. In order to optimize treatment with PLD, we assessed the prognostic and predictive factors for efficacy of PLD.

Methods

Seventeen patients treated with PLD 30 or 40 mg/m² underwent pharmacokinetic sampling during the first cycle of treatment. PLD exposure was calculated. An univariate analysis was performed with the variables: hand–foot syndrome, mucositis, rash, neutropenia, age, tumor type, number of previous therapies, ECOG performance status and progression-free survival (PFS). Candidate variables with p ≤ 0.1 were selected for the multivariate analysis.

Results

Based on the results of the multivariate analysis, the PLD exposure (log AUC) was higher in patients who experienced rash (p = 0.002) and mucositis (p = 0.001) compared to those who did not have these adverse events. The development of hand–foot syndrome was significantly related to a lower risk of disease progression (HR 0.1; 95 % CI 0.02–0.64). Patients with an ECOG status of 0 had a longer PFS than the patients with an ECOG status of 1 (HR 5.4; 95 % CI 1.3–22.8). Moreover, PLD exposure (ln AUC) was also positively related to PFS (HR 0.001; 95 % CI 0.00–0.42).

Conclusions

The extent of the exposure to PLD was correlated with more adverse events and longer PFS. This has important clinical implications, since dose reductions or interruptions might thus negatively affect treatment outcomes. More attention should be paid to preventive and supportive measures of adverse events of PLD to keep the exposure to PLD as high as possible.     

Evaluation of effects on the peritoneum after intraperitoneal α-radioimmunotherapy with (211)At

The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70 μm) and the short half-life (7.21 h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.     

Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis

The role of the fibronectin receptor, α(5)β(1)-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α(5)β(1)-integrin led to a direct association of α(5)-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α(5)β(1)-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α(5)β(1)-integrin inhibition on tumor cell invasion, indicating that α(5)β(1)-integrin is upstream of c-Met, Src and FAK. Inhibition of α(5)β(1)-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α(5)β(1)-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α(5)β(1)-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.     

Role of non-receptor and receptor tyrosine kinases (TKs) in the antitumor action of α-difluoromethylornithine (DFMO) in breast cancer cells

We have shown that administration of α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis, reduces the invasive and metastatic properties of MDA-MB−435 breast cancer cells while activating multiple signal transduction pathways, including MAPK, Stat3, Stat1, and JNK. Since the activity of these signaling mechanisms is frequently regulated by upstream tyrosine kinases (TKs), we tested whether non-receptor and receptor TKs may be involved in the signaling and biological effects of DFMO in MDA-MB−435 cells. Treatment with DFMO (1 mM for 48 h) did not affect Src phosphorylation (Tyr 416). Administration of the Src-family members inhibitor PP-1 (1 μM), blocked Src phosphorylation in the absence and in the presence of DFMO, but did not block the signaling effects of DFMO (increased phosphorylation of Stat3, Stat1, ERK and JNK). PP-1 treatment, on the other hand, inhibited the invasiveness of MDA-MB−435 cells in matrigel and potentiated the anti-invasive effect of DFMO. Next, we focused on the role of receptor TK. Western analysis of cell lysates from MDA-MB−435 cells failed to show the presence of EGF-R and HER-2neu but demonstrated the expression of c-Met, the receptor for hepatocyte growth factor (HGF). Therefore, we tested the effect of DFMO on the HGF/c-Met pathway which is strongly implicated in the progression of human breast cancer. We found that DFMO treatment blocked HGF-induced c-Met phosphorylation in MDA-MB−435 cells, suggesting that its anti-invasion action may be mediated, at least in part, by blocking c-Met signaling. Next, we showed that 1 mM DFMO suppressed HGF induced invasiveness of MDA-MB−435 cells in matrigel. Combination administration of DFMO with suboptimal doses of PHA-665752, a specific c-Met inhibitor, reduced invasiveness to an even greater extent than the individual treatment. These findings indicate that Src-family members, while not involved in DFMO action, promote invasiveness of breast cancer cells and their inhibition may enhance the antitumor effect of PA depletion. Our data also point to inhibition of HGF/c-Met pathway as a possible novel approach to enhancing the antitumor action of DFMO.     

Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome)

BACKGROUND: There is limited published evidence regarding the efficacy of total skin electron beam radiation for patients with the diffuse erythrodermic form of mycosis fungoides. METHODS: Forty-five patients with erythrodermic mycosis fungoides were managed at McMaster University in Hamilton, Ontario, Canada (n=34), and at Yale University (n=11) between 1970 and 1996. All received radiation without neoadjuvant, concomitant, or adjuvant therapies. The median age was 67 years (range, 42-84 years). The male-to-female ratio was 2.2. Fifteen received radiation for the treatment of newly diagnosed disease. There were 28 with Stage III (T4 N0-1 M0), 13 with Stage IVA (T4 N2-3 M0), and 4 with Stage IVB (T4 N0-3 M1) disease, and 21 had blood involvement. The median radiation dose was 32 gray (Gy) (range, 4.8-40 Gy). The median treatment time was 21 days (range, 3-125 days). A technically more intense method of radiation (32-40 Gy and 4-6 MeV electrons) was administered to 23 patients. RESULTS: All patients responded. The rate of complete cutaneous remission was 60%, with 26% remaining progression free at 5 years. Remission was associated with more intense radiation (P=0.014 in multivariate analysis with adjustment for blood and staging information). With the more intense radiation, 74% attained remission, with 36% remaining progression free at 5 years. For 8 patients with Stage III disease without blood involvement, all entered remission, with 69% remaining progression free at 5 years. Twenty of 30 deaths were related to mycosis fungoides. The median overall survival was 3.4 years, with a 10-year estimate of 28%. The median cause specific survival was 5 years, with a 10-year estimate of 43%. Both overall and cause specific survival were associated with an absence of blood involvement (both P<0.03 in multivariate analysis). Age was not a significant factor. Toxicities of radiation were acceptable when radiation was administered over 6-9 weeks at 5 fractions per week. CONCLUSIONS: Total skin radiation is an efficient monotherapy for patients with erythrodermic mycosis fungoides. With more intense radiation, the rate of cutaneous remission is 74%, and 27% remain progression free at 10 years. Radiation may be most efficacious in Stage III, with no blood involvement. When there is blood, lymph node, or visceral involvement, combined modality therapies should be explored.     

Expression of α-taxilin in hepatocellular carcinoma correlates with growth activity and malignant potential of the tumor

The membrane traffic system has been recognized to be involved in carcinogenesis and tumor progression in several types of tumors. α-taxilin is a newly identified membrane traffic-related molecule, and its up-regulation has been reported in embryonic and malignant tissues of neural origin. In the present study, we analyzed the expression of α-taxilin in relation to clinicopathological features of hepatocellular carcinomas (HCC) and proliferative activity of the tumor determined by proliferating cell nuclear antigen labeling index (PCNA-LI). Twenty-nine surgically resected nodules of HCC (8 well-, 11 moderately-, and 10 poorly-differentiated) were studied. Fifteen cases showed 'strong staining', while 14 cases showed 'weak staining' for α-taxilin. A significantly higher expression of α-taxilin was observed in less-differentiated (p=0.005), and more invasive (p=0.016) HCCs. The 'strong staining' group showed significantly higher PCNA-LI than the 'weak staining' group (the medians of PCNA-LI were 59.4% vs. 14.4%, p<0.0001). We also evaluated the expression of α-taxilin in hepatoma cell lines (PLC/PRF/5, Hep G2 and HuH-6) in association with cell proliferation. The expression levels of α-taxilin protein were correlated with their growth rates. In conclusion, the expression of the α-taxilin protein was related with an increased proliferative activity and a less-differentiated histological grade of HCC. α-taxilin may be involved in cell proliferation of HCC, and its expression can be a marker of malignant potential of HCC.