Non-small Cell Research Articles

Furanoditerpenes from Pterodon pubescens benth with selective in vitro anticancer activity for prostate cell line

Activity guided fractionation of Pterodon pubescens Benth. methylene chloride-soluble fraction afforded novel 6α-acetoxi 7β-hydroxy-vouacapan 1 and four known diterpene furans 2, 3, 4, 5. The compounds were evaluated for in vitro cytotoxic activities against human normal cells and tumour cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-H460 (lung, non-small cells), OVCAR-03 (ovarian), PC-3 (prostate), HT-29 (colon), 786-0 (renal), K562 (leukemia) and NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance). Results were expressed by three concentration dependent parameters GI50 (concentration that produces 50% growth inhibition), TGI (concentration that produces total growth inhibition or cytostatic effect) and LC50 (concentration that produces -50% growth, a cytotoxicity parameter). Also, in vitro cytotoxicity was evaluated against 3T3 cell line (mouse embryonic fibroblasts). Antiproliferative properties of compounds 1, 4 and 5 are herein reported for the first time. These compounds showed selectivity in a concentration-dependent way against human PC-3. Compound 1 demonstrated selectivity 26 fold more potent than the positive control, doxorubicin, for PC-3 (prostrate) cell line based on GI50 values, causing cytostatic effect (TGI value) at a concentration fifteen times less than positive control. Moreover comparison of 50% lethal concentration (LC50 value) with positive control (doxorubicin) suggested that compound 1 was less toxic.

Plasminogen activator inhibitor variants PAI-1 A15T and PAI-2 S413C influence lung cancer prognosis

The plasminogen pathway plays an important role in the behavior of many tumors including lung cancer. Hence genetic variants encoding plasminogen activator (PLAU), plasminogen receptor (PLAUR), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) may contribute to lung cancer prognosis. To investigate this proposition we genotyped PAI-1 A15T, PLAU L141P, PLAUR L317P and PAI-2 S413C variants in 698 patients with lung cancer, 522 with non-small cell (NSCLC) and 176 with small cell lung cancer (SCLC). PAI-1 A15T was significantly associated with overall survival (OS), with carriers of variant alleles having a worse prognosis (hazard ratio (HR) = 1.14; 95% confidence interval [CI]: 1.03–1.26). An association was also detected between OS in NSCLC and carrier status for PAI-2 413C (HR = 1.13; 95% CI: 1.01–1.24). These common genetic variants identified warrant further evaluation as promising prognostic markers of patient outcome.

Prospective Study of Physical Activity and Lung Cancer by Histologic Type in Current, Former, and Never Smokers

Increased physical activity has been associated with decreased lung cancer risk. However, no previous investigation has examined physical activity in relation to lung cancer histologic types by smoking status. The authors investigated these relations in the National Institutes of Health-AARP Diet and Health Study among 501,148 men and women aged 50-71 years at baseline in 1995-1996. During follow-up to 2003, 6,745 lung carcinomas occurred (14.8% small cell, 40.3% adenocarcinoma, 19.7% squamous cell, 6.1% undifferentiated large cell, 7.2% non-small cell not otherwise specified, and 11.8% carcinoma not otherwise specified). Among former smokers, the multivariate relative risks of small cell, adenocarcinoma, squamous cell, and undifferentiated large cell carcinomas comparing the highest with the lowest activity level (> or =5 times/week vs. inactive) were 0.93 (95% confidence interval (CI): 0.67, 1.28), 0.79 (95% CI: 0.67, 0.94), 0.73 (95% CI: 0.57, 0.93), and 0.61 (95% CI: 0.38, 0.98), respectively. Among current smokers, corresponding values were 0.77 (95% CI: 0.58, 1.02), 0.76 (95% CI: 0.61, 0.95), 0.85 (95% CI: 0.65, 1.11), and 1.10 (95% CI: 0.69, 1.78). In contrast, physical activity was unrelated to lung carcinoma among never smokers (P(interaction) between physical activity and smoking for total lung carcinomas = 0.002). The inverse findings among former and current smokers in combination with the null results for physical activity among never smokers may point toward residual confounding by cigarette smoking as an explanation for the relations observed.

The antitumor activity of an anti‐CD54 antibody in SCID mice xenografted with human breast, prostate, non‐small cell lung, and pancreatic tumor cell lines

We have previously described the development and testing of a monoclonal anti-human CD54 antibody (UV3) in SCID mice xenografted with human multiple myeloma, lymphoma, and melanoma cell lines. In all 3 cases, UV3 was highly effective at slowing the growth of tumors and/or prolonging survival. Since CD54 (ICAM-1) is up-regulated on many different types of cancer cells, we have now investigated the anti-tumor activity of UV3 in several other CD54(+) epithelial tumors. A panel of 16 human breast, prostate, non-small cell (NSC) lung, and pancreatic tumor cell lines was examined for reactivity with UV3, and 13 were positive. A representative CD54(+) cell line from each cancer was grown subcutaneously in SCID mice. Once the tumors were established, UV3 was administered using different dose regimens. UV3 slowed the growth of all 4 tumors, although it was not curative. When UV3 or gemcitabine were administered to SCID mice xenografted with a NSC lung tumor cell line or a pancreatic tumor cell line, UV3 was as effective as the chemotherapy alone. When gemcitabine and UV3 were administered together, the best anti-tumor responses were observed. UV3 has been chimerized (cUV3) and both toxicology studies and clinical trials are planned to assess the safety and activity of cUV3 in patients with one or more of these tumors.

OR2,6 Interrelationship between somatostatin/dopamine pathways and growth factors in non-small lung cancer cells

OR2,6 Interrelationship between somatostatin/dopamine pathways and growth factors in non-small lung cancer cells

Interaction of Ganoderma Triterpenes with Docetaxel and Cisplatin in Cytotoxicity against Human Carcinoma Cells

AIM: Ganoderma triterpenes (GTS) are the main components with cytotoxicity in Ganoderma lucidum, a popularly used traditional Chinese Medicine (TCM) for complementary cancer therapy. The present study was designed to investigate the possible interaction between Ganoderma triterpenes and chemotherapeutics. METHODS: Cultures of human cervical carcinoma HeLa cells and human non-small lung carcinoma A549 cells were used. The cytotoxic effects of GTS in combination with docetaxel (TXT) or cisplatin (CDDP) on cells were examined and the combination effects were analyzed by the Chou and Talalay combination index method. RESULTS: The combinations targeting GTS with TXT resulted in a synergistic interaction in HeLa cells and an additive interaction in A549 cells. While, in both HeLa and A549 cells, the interactions between GTS and CDDP depended on the relative potency of their cytotoxicity. The interaction was antagonism when the cytotoxicity of GTS or CDDP was stronger than that of the other and was synergism when the cytotoxicity of the two medicines was similar. CONCLUSION: GTS could enhance the cytotoxicity of some kinds of chemotherapeutics but not all chemotherapeutics against human carcinoma cells.

Gaps in Optimal Care for Lung Cancer

Lung cancer is the leading cause of cancer death in Australia, but little is known about how Australian patients with this disease are managed. Lung cancer patients diagnosed from November 1, 2001 to December 31, 2002 were identified through the population-based New South Wales Central Cancer Registry. Information was collected on diagnosis, staging, referrals, and treatment. Cross-tabulations and logistic regression examined factors related to not receiving cancer-specific therapy. There were 2931 potentially eligible patients registered by the Central Cancer Registry and completed questionnaires were obtained for 1812 patients (62%); median age 71 years and 66% men. The pathology was non-small cell in 71%, small cell in 15% and not confirmed in 13% of patients. Eleven percent of patients did not see a lung cancer specialist and 33% received no cancer-specific therapy after initial diagnosis. Treatment utilization rates were 17% for surgery, 39% for radiotherapy, and 30% for chemotherapy. Factors significantly associated with having no cancer-specific therapy included female gender, older age, weight loss, poorer performance status, advanced or unknown disease stage, and consultation with a low patient volume lung cancer specialist or a non-lung cancer specialist. The median survival was 172 days and 2-year crude survival was 17%. Treatment patterns were in broad concordance with present national guidelines. Nevertheless, a significant proportion of lung cancer patients did not receive cancer-specific therapy. Treatment decisions should be multidisciplinary and decision-makers should include experienced lung cancer specialists.

Altered calcium-homeostasis of cisplatin-resistant non small cell (NSLC) and small cell lung (SCLC) cancer cells

22185 Background: Chemotherapy in advanced lung cancer often leads to encouraging responses, but, in the course of the treatment, resistance to chemotherapy ultimately limits the life expectancy of the patient. The mechanisms of resistance to cisplatin, which is one of the most effective and most frequently used chemotherapeutics in lung cancer, are still not understood. We aimed at investigating if the intracellular Ca2+-homeostasis may be related to cisplatin resistance. Methods: The squamous cell lung carcinoma cell line EPLC and the small cell lung cancer cell line H1339 were exposed to cisplatin analogue to the in vivo pharmacokinetics. Changes in the cytoplasmic Ca2+-concentration ([Ca2+]c) were recorded using fluorescence microscopy and protein expression was quantified using Western Blot analysis and immuno-fluorescence. Results: Four “cycles” of cisplatin led to partial resistance in EPLC and H1339 cells. The partial resistance could be mimicked by buffering [Ca2+]c using BAPTA. In the resistant clones of both cell types, the Ca2+-content of the endoplasmic reticulum (ER) was decreased. In EPLC cells, this was correlated with an increased expression of the inositol-1,4,5-trisphosphate receptor (IP3R). In H1339 cells, the decrease Ca2+-content of the ER was correlated with a decreased expression of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Using the siRNA technique, we could show that the modified expression of the respective proteins in fact altered the cisplatin sensitivity. Conclusions: We conclude that a decreased Ca2+- content of the ER contributes to cisplatin resistance and show for the first time that upregulation of the IP3R and decreased expression of SERCA are involved in cisplatin-resistance. No significant financial relationships to disclose.

A phase II trial of SNS-595 in women with platinum resistant epithelial ovarian cancer

5582 Background: SNS-595 is under clinical investigation in acute leukemia and ovarian cancer. Clinical responses have been observed in these indications, and in non-small cell and small cell lung cancers. SNS-595 is a replication-dependent DNA damaging agent that causes irreversible G2 arrest and apoptosis via DNA intercalation and topoisomerase II inhibition. A phase 2 study of single agent SNS-595 in ovarian cancer was initiated based on phase 1 clinical activity in patients (pts) with ovarian cancer, including one partial response (PR). Methods: Pts had advanced platinum resistant (progressed during or relapsed within 6 months of platinum based therapy) epithelial ovarian cancer who had progressive disease after 1 or 2 prior platinum containing regimens; pts could have received an additional biologic or non-platinum therapy after becoming platinum-resistant. A GOG PS of 0–1 and adequate hematologic, hepatic and renal status were required. Pts received 48 mg/m2 SNS-595 by 10 minute IV infusion on Day 1...

Risk of lung cancer in Hodgkins (HL), non-Hodgkins (NHL) lymphoma and chronic lymphocytic leukemia (CLL) patients (pts): Analysis of the Surveillance Epidemiology and End Results (SEER) data

8611 Background: Development of lung cancer(LC) in pts with lymphoma and CLL has been observed, although the risk of LC in these pts is not well characterized. We conducted an analysis of the SEER data to assess the risk of LC and risk of other second primary cancers (SPC) in these pts and define the pts likely to develop LC. Methods: Pts with HL, NHL and CLL diagnosed between 1973–1997 with follow up through 2002, in the SEER data were included. Standardized Incidence Ratios (SIRs) were calculated to assess the risk of developing LC and SPC in these pts compared to the general population. The demographics of pts with subsequent LC were also analyzed. Results: 83,423 pts with HL, NHL and CLL were identified, of whom 1825 (2%) pts developed LC. A 300% increase in LC incidence was observed in HL (SIRs - 3.01; Males- 2.88, Females- 3.32), 30% increase in NHL (SIRs- 1.31; Males- 1.23, Females- 1.44) and 60% increase in CLL pts (SIRs- 1.59; Males-1.60, Females- 1.54), whereas the incidence of other SPC was increased by 92%,8% and 6% in HL, NHL and CLL pts respectively. LC occurred more often than expected in pts < 50 years in each of the lymphoma categories (SIRs for HL- 4.57; NHL- 2.25; CLL- 3.42) but not in pts 70 years or older at lymphoma/CLL diagnosis. The median time to development of LC was HL- 9 years, NHL- 6 years and CLL- 5 years. 92% of LCs were non-small cell and 8% were small cell in NHL and CLL pts, while in HL pts it was 85% and 15%. The median survival of pts following diagnosis of LC ranged from 5–9 months. Conclusions: The risk of LC is significantly higher in pts with HL, NHL and CLL compared to the general population, especially in pts < 50 yrs. The biological factors underlying this increased risk are unclear. These data have important implications regarding screening for LC in these pts. No significant financial relationships to disclose.

Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Secretion Caused by Squamous Cell Carcinoma of the Nasopharynx: Case Report

The Paraneoplastic syndromes include the disorders that accompany benign or malignant tumors but are not directly related to mass effects or invasion by the primary tumor or its metastases. Neoplastic cells can produce a variety of peptides that exert biologic actions at local and distant sites and can elicit responses that cause a variety of hormonal, hematologic, dermatologic and neurologic symptoms. Almost every type of malignancy has the potential to produce hormones or cytokines or to induce immunologic responses. Lung cancers, both non-small cell and small cell, are capable of producing a variety of paraneoplastic syndromes. The majority of such syndromes are caused by small cell carcinomas, including many endocrinopathies. Syndrome of inappropriate antidiuretic hormone (SIADH) has been commonly associated with small cell carcinoma and is often seen in these patients. However, SIADH associated with squamous cell carcinoma has rarely been reported on, and the mechanism for this rare association is still unknown. We present here a case of a 77-yr-old man who developed SIADH caused by squamous cell carcinoma of the nasopharynx.

Lung cancer resection rate in south Manchester: is it comparable to international standards? Results of a prospective tracking study

The UK has been reported to have the lowest resection and survival rates for lung cancer patients. These reports were based largely on retrospective data from the cancer registry and are now outdated. To monitor the present day surgical resection rate at our institution all newly diagnosed cases of lung cancer presenting to us were enrolled into a prospective tracking study. From September 2003 to March 2005 all suspected primary lung cancer referrals to the North West Lung Centre were tracked to identify patients with newly diagnosed lung cancer. The histology of 247 patients confirmed to be new lung cancer cases were small cell (SCLC), non-small cell (NSCLC) and mixed cancers in 33 (16%), 170 (83.5%) and 1 (0.5%) patients, respectively, while 43 patients had no histological confirmation. Overall, 43 patients (17%) underwent surgery while chemotherapy and radiotherapy were used in 91 (38%) and 43 (17%), respectively. Out of 170 confirmed NSCLC patients, 43 (25%), 65 (38%) and 27 (16%) patients underwent surgery, chemotherapy and radiotherapy, respectively. The remaining 35 (20%) did not receive any treatment because of patient wishes or poor condition. The surgical resection rates were 17% for all lung cancers and 25% for NSCLC. Current surgical resection rates at the South Manchester University Hospital are comparable to international standards. Similar data from the rest of the UK are required to determine the national resection rate, which may not be as low as once thought to be.

Antiproliferative properties of polyketides isolated from Virola sebifera leaves

An activity-guided fractionation of Virola sebifera Aubl. methylene chloride-soluble fraction provided novel 3,5-dihydro-2-(1'-oxo-3'-hexadecenyl)-2-cyclohexen-1-one (3), two known lignans (1, 2) and dehydro hexadecanoyl resorcinol (4). Isolation and purification were conducted with the application of column chromatography and structures were assigned by spetral analysis (1D and 2D NMR, HREIMS). Compounds 1-4 were evaluated for cytotoxic activities against human tumour cell lines UACC62 (melanoma), MCF-7 (breast), NCI 460 (lung, non-small cells), OVCAR03 (ovarian), PC-03 (prostate), HT-29 (colon), 786-0 (renal) and NCI-ADR (breast expressing phenotype multiple drugs resistance) in vitro. The new polyketide (3) showed selectivity against human OVCAR03 and NCI-ADR cell lines, ranging from 2 to 4 microg/mL.

Number of lymph nodes harvested from a mediastinal lymphadenectomy: Results of the randomized, prospective ACOSOG Z0030 trial

7555 Background: Lymph node status is a major determinant of stage and survival in patients with lung cancer; however, little information is available about the yield of a mediastinal lymphadenectomy done at the time of pulmonary resection. Methods: The ACOSOG Z0030 trial is a prospective, randomized trial of mediastinal lymph node sampling versus complete mediastinal lymphadenectomy during an operation for early stage lung cancer. Total enrollment from July 1999 to February 2004 was 1,111 patients, of which 1,023 were eligible and/or evaluable. There were 524 patients who underwent complete mediastinal lymph node resection after randomization to this arm that were declared eligible and/or evaluable with lymph node data available. The number of lymph nodes examined from each station was collected beginning in January 2002. Prospectively collected data from these patients was analyzed to determine the number of lymph nodes obtained. Results: Median age was 67 (range 37–87) and 267 (52%) were men. Histology was squamous cell in 141 (27%), adenocarcinoma in 227 (44%), large cell in 22 (4%), bronchoavelolar in 32 (6%) and other non-small cell in 99 (19%). There were 317 right sided cancers and 207 left sided cancers. For lymphadenectomy for cancers in the right lung the yield from station 2R was a median of 2 lymph nodes (range 1 to 15), station 4R was 2 (1 –17), station 7 was 2 (1–24), station 8 was 1 (1–5), station 9 was 1 (1–6) and station 10R was 1 (1–10). For lymphadenectomy for cancers on the left side the yield from station 2L was 2 (1–4), station 4L was 1 (1–12), station 5 was 2 (1–18), station 6 was 2 (1–11), station 7 was 2 (1–16), station 8 was 1 (1–3), station 9 was 1 (1–8) and 10L was 2 (1–12). The total number of lymph nodes or fragments obtained for right sided cancers was a median of 13.5 (range 1 to 56) and for left sided tumors 15 (range 4 to 81). Conclusions: Although high variability exists in the actual number of lymph nodes obtained from various nodal stations, a complete mediastinal lymphadenectomy should obtain one or more lymph nodes from each mediastinal station. Adequate mediastinal lymphadenectomy should include exploration and remove of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right sided cancers and stations 4L, 5, 6, 7, 8 and 9 for left sided cancers. No significant financial relationships to disclose.

Oral vinorelbine in first line treatment of NSCLC in elderly: Updated results of a low dose schedule in a single institution experience

18192 Background: Oral Vinorelbine has been reported as an effective treatment option for advanced NSCLC in patients not suitable for CDDP containing schedules. Methods: With the aim to improve the toxicity profile of oral Vinorelbine therapy in the elderly setting, from 01/2004 to 05/2006, 31 patients with stage IIIB-IV NSCLC were treated with single agent oral Vinorelbine at the dose of 60 mg/m2 day 1,8,15 every 3 weeks. Median age of patients was 75 (range 65 to 82) and M/F ratio 1,6. All patients were untreated and received oral Vinorelbine as first line chemotherapy. 24/31 pts were first diagnosed and not suitable for surgery (14/24 locally advanced, 4/24 not operable for comorbidity, 6/24 stage IV at diagnosis), 7/31 recurring after surgery. Pathology reports 15/31 adenocarcinoma, 9/31 squamous, 7/31 non-small cells (citology). Sites of distant metastases were as follow: liver in 13%, bone in 16%, mediastinal lymph nodes in 71%. Median Karnofsky performance status was 80 (range 60–90). Results: Adverse event were experienced by 35% of patients, but were generally mild (grade 1–2). In particular fatigue was reported by 13%, parhestesias by 16%, gastrointestinal disconfort (mild nausea/diarrea) by 26%, costipation/abdominal pain by 10%, trombocytopenia by 6%; no patient experienced anorexia, emesis nor febrile neutropenia. Dose reduction was never required.Complete reversal of adverse effects was always documented. No patient experienced CR; 6/31 (19%) PR and 8/31 (26%) SD were reported with clinical benefit in 14/31 patients (45%). Median time to progression and overall survival were 4,2 and 9 months, not different from data reported in recent literature for higher intensity schedule (Gridelli C, et al.: Eur J Cancer 40:2424–43, 2004) Conclusions: Treatment with oral Vinorelbine at the 60 mg/m2 day 1,8,15 every 3 weeks schedule has a low toxicity profile and seems to be better tolerated than the conventional dose of 80 mg/m2, representing a valide alternative for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

Prognostic significance of folate metabolism polymorphisms for lung cancer.

Functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) of folate metabolism genes can influence the methylation of tumour suppressor genes, thereby potentially impacting on tumour behaviour. To investigate whether such polymorphisms influence lung cancer survival, we genotyped 14 nsSNPs mapping to methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR); DNA methyltransferase (DNMT2), methylenetetrahydrofolate dehydrogenase (MTHFD1) and methenyltetrahydrofolate synthetase (MTHFS) in 619 Caucasian women with incident disease, 465 with non-small cell (NSCLC) and 154 with small cell lung cancer (SCLC). The most significant association detected was with MTHFS Thr202Ala, with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.49; 95% confidence interval: 1.14–1.94). Associations were also detected between overall survival (OS) in SCLC and homozygosity for MTHFR 222Val (HR=1.92; 1.03–3.58) and between OS from NSCLC and MTRR 175Leu carrier status (HR=1.36; 1.06–1.75). While there is evidence that variation in the folate metabolism genes may influence prognosis from lung cancer, current data are insufficiently robust to distinguish individual patient outcome.

Warning Flags for Erythropoiesis-Stimulating Agents and Cancer-Associated Anemia

A recent U.S. Food and Drug Administration (FDA) alert has raised further concerns about potential adverse effects of erythropoiesis-stimulating agents (ESAs) in anemic cancer patients who are not receiving chemotherapy [1]. The warning was issued following interim analysis of an investigator-led phase III trial of 989 patients with head and neck cancers randomized to receive darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) or placebo (Danish Head and Neck Cancer Group [DAHANCA] 10 study, http://www. dahanca.dk). The enrolled patients were anemic but were not receiving chemotherapy. The trial data showed that darbepoetin alfa was associated with a higher mortality than with placebo (hazard ratio, 1.25; confidence interval [CI], 1.04–1.51) and, furthermore, darbepoetin alfa did not reduce the need for blood transfusion [2]. Hard on the heels of the darbepoetin alfa alert, Roche announced that it had temporarily suspended recruitment into its phase II dose-finding study with Continuous Erythropoietin Receptor Activator (CERA) in anemic patients with advanced nonsmall lung cell cancer (NSCLC) receiving chemotherapy [3]. Very recently, an unplanned safety analysis resulted in closure of a randomized placebo-controlled trial of epoetin alfa in NSCLC patients with disease-related anemia [4]. This analysis suggested poorer overall survival in patients with NSCLC treated with erythropoietin (Epo) [4]. Anemia in cancer patients has a multifactorial etiology. Anemia may develop secondary to impaired production of Epo or a blunted response of erythroid precursors to Epo [5]. Anemia may be exacerbated by chronic blood loss from tumor sites or be secondary to chemotherapy and radiotherapy. Debilitating fatigue, if it is secondary to anemia, can be managed by blood transfusions or ESAs to improve the quality of life (QOL) for anemic cancer patients. Interestingly, the effect of Epo therapy on QOL as a prospective outcome is not entirely consistent [6, 7]. Darbepoetin alfa is a hyperglycosylated Epo analog with an extended serum half-life [8] compared with available recombinant human Epos (epoetin alfa [Procrit, Ortho Biotech, Bridgewater, NJ; Epogen, Amgen; or Eprex, Janssen-Cilag Ltd, High Wycombe, U.K.] and epoetin beta [NeoRecormon, Roche, Basel, Switzerland]). CERA incorporates methoxy-polyethylene glycol polymers, which increase its mass to 60 kDa, twice that of Epo, and substantially prolong its half-life to about 135 hours. Darbepoetin alfa and CERA therefore have the therapeutic advantage of requiring less frequent administration for anemia management. Previous reports have suggested that ESA therapy may be harmful to some groups of cancer patients. Henke and colleagues [9] described the outcome of epoetin beta treatment in a randomized trial of 351 anemic head and neck cancer patients undergoing radiotherapy. The therapeutic goal was normalization of hemoglobin to 14 g/dl in men and 13 g/dl in women. Unexpectedly, locoregional progression-free survival was worse in the Epo treatment arm compared with placebo. In the same year, another random-

Clinical outcome in patients with intramedullary spinal cord metastases from lung cancer

Intramedullary spinal cord metastases (ISCM) are uncommon and present with rapidly progressing neurological deficits. The objective of this study was to determine the rate, duration of neurological response and survival after radiation therapy. We have retrospectively reviewed the clinical outcome of six cases with a diagnosis of ISCM from primary lung cancer, non-small cell (NSCLC) (n=3) and small cell (SCLC) (n=3). Total radiation dose ranged from 27 Gy/5 fr to 40 Gy/20 fr. Ambulation was preserved in 3 patients and partially recovered in one. Five out of the six patients (83%) showed improvement in neurological signs/symptoms with a mean duration of 17.2 days (max: 40 days; min: 6 days). Median survival time was 5 months (confidence interval (CI) 95%: 0-12) for NSCLC and 5 months (CI 95%: 4-6) for SCLC. Although radiation response rate is high, the interval free of neurological progression is very short. A therapeutic approach should be considered for each individual.

Additive Cytotoxic Effect of Apoptin and Chemotherapeutic Agents Paclitaxel and Etoposide on Human Tumour Cells

Gene therapy experiments in animal models have shown that apoptin expression results in tumour regression without any significant side effects. Therefore, apoptin is regarded as a potential anticancer drug for clinical applications. In this study, we analysed whether chemotherapeutic agents combined with apoptin treatment could result in enhanced cytotoxicity in human tumour cell cultures. Combined treatment with recombinant adenovirus AdAptVP3 expressing apoptin and etoposide clearly showed an additive cytotoxic effect on human osteosarcoma U2OS cells. Paclitaxel treatment combined with apoptin expression significantly inhibited the survival of p53-positive human osteosarcoma U2OS and non-small lung carcinoma A549 cells, p53-negative human osteosarcoma Saos-2 cells and p53-mutant human prostate cancer Du145 cells, already at low doses of the chemotherapeutic agent. Our results indicate that the cytotoxicity-enhancing action by the tumour-specific apoptin in combination with chemotherapeutic agents might offer an effective and safe antitumour therapeutics.

Voltage-Gated Sodium Channels: New Targets in Cancer Therapy?

Early detection and treatment of cancers have increased survival and improved clinical outcome. The development of metastases is often associated with a poor prognostic of survival. Finding early markers of metastasis and developing new therapies against their development is a great challenge. Since a few years, there is more evidence that ionic channels are involved in the oncogenic process. Among these, voltage-gated sodium channels expressed in non-nervous or non-muscular organs are often associated with the metastatic behaviour of different cancers. The aim of this review is to describe the current knowledge on the functional expression of voltage-gated sodium channels and their biological roles in different cancers such as prostate, breast, lung (small cells and non-small cells) and leukaemia. In the conclusion, we develop conceptual approaches to understand how such channels can be involved in the metastatic process and conclude that blockers targeted toward these channels are promising new therapeutic solutions against metastatic cancers.