Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Trends in the use of implantable cardioverter defibrillators in Australia: a 10-year nationwide study from 2000-2009.

BACKGROUND: Implantable cardioverter defibrillators (ICD) have been demonstrated to reduce mortality in survivors of life-threatening arrhythmias (secondary prevention) and in patients at increased risk of sudden cardiac death (primary prevention). Other nations have reported significant increases in ICD use in recent years. AIM: To investigate Australian nationwide trends of ICD procedures over a 10-year period (2000-2009). METHODS: A retrospective analysis of the Australian Institute of Health and Welfare's National Hospital Morbidity Database was performed to determine the annual number of ICD implantation and replacement procedures between 2000 and 2009. Rates were calculated using Australian Bureau of Statistics data on the annual estimated population. Time trends in the yearly procedure number and rate were analysed using negative binomial regression models with comparisons made by age and sex. RESULTS: The number of new ICD implantations increased from 708 to 3198 procedures between 2000 and 2009. Replacement procedures increased from 290 to 1378. The implantation rate (per million) increased from 37.0 to 145.6 and the replacement rate from 15.1 to 62.7. When rates were adjusted for age and sex, the implantation rate increased annually by 15.8% and the replacement rate by 16.6% (P < 0.0001). Procedures occurred most commonly in men (implantations: 80.1%; replacements: 78.0%) between ages 70-79. CONCLUSIONS: ICD procedures increased significantly in Australia between 2000-2009. Despite these increases, other studies have suggested ICD devices are currently under-utilised. During the study period, males accounted for the majority of ICD procedures. While there are numerous reasons for this, it is not known if device under-use is more common in females.

Automated quantification of atrial fibrillation complexity by probabilistic electrogram analysis and fibrillation wave reconstruction.

The analysis of high-density activation maps of atrial fibrillation (AF) provides fundamental insights into the fibrillation wave propagation patterns and thus the mechanisms of AF. Current annotation of local activations in unipolar atrial electrograms and the construction of fibrillation waves require labor-intensive manual editing. To enhance the possibilities for spatiotemporal analysis of AF, we developed a rapid and fully automated procedure to accurately identify local, intrinsic atrial deflections and construct fibrillation waves based on these deflections. In this study, the automated procedure was validated using manually annotated electrograms and wave maps. We show that the novel procedure accurately detects intrinsic deflections (sensitivity=87%, positive predictive value=89%) and that reconstructed wave maps correlate well with manually edited wave maps in terms of number of waves (r=0.96), intra-wave conduction velocity (r=0.97), AF cycle length (r=0.97), and wave size (r=0.96) (p<0.01 in all cases). The automated procedure is therefore an adequate substitute for manual annotation.

Evidence-based management of heart failure in clinical practice: a review of device-based therapy use.

BACKGROUND: Heart failure is a growing health issue and is associated with significant mortality risk. Device therapy is efficacious in preventing sudden death in patients with heart failure; however, this evidence comes from rigorous clinical trials. It is unclear how device therapy is utilized in 'real-world' practice. The primary objective was to characterize patterns of device use in patients with heart failure at risk of sudden death and to identify barriers to guideline-driven prescription of implantable cardioverter-defibrillators. METHODS: We report a cross-sectional study of patients attending general cardiology clinic over a 3-month period. RESULTS: Of 1003 consecutive patients attending the cardiology clinic, 176 had heart failure. Of these, 66 were potentially eligible for device therapy, but only 16 of these had actually undergone device implantation. Potentially eligible non-recipients were older (P < 0.001), more likely to have ischaemic cardiomyopathy (P= 0.002), less likely to be prescribed spironolactone (P= 0.005) or warfarin (P= 0.02), and less likely to have a widened QRS > 120 ms (P= 0.005). There was a high prevalence of underuse of evidence-based pharmacotherapies among patients with heart failure. CONCLUSION: There is substantial underuse of device therapy in patients with heart failure. Strikingly, whereas patients with symptoms of heart failure were more likely to receive a device, those being managed for ischaemic heart disease were not. There is also a high prevalence of failure to prescribe evidence-based pharmacotherapy in a tertiary hospital general cardiology clinic. This may be explained in part by the lack of a patient database to record treatment contraindications and to alert clinicians to possible gaps in patient therapy.

In vitro and in vivo effects of vardenafil (a PDE-5 Inhibitor) on corpus cavernosal smooth muscle relaxation in diabetic rabbits.

INTRODUCTION: Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the development of erectile dysfunction (ED). Vardenafil, a phosphodiesterase type 5 inhibitor has been used to treat ED. The aim of this study was to assess the in vitro and in vivo effects of vardenafil on diabetic rabbit CSMR. METHODS: Organ bath studies were used. RESULTS: Sodium nitroprusside (SNP)- and electrical field stimulation (EFS)-induced CSMR in diabetic rabbits given the vehicle was significantly impaired when compared with controls. The in vitro addition of vardenafil significantly enhanced SNP-induced CSMR in diabetic animals given the vehicle. SNP-induced CSMR in diabetic animals given in vivo vardenafil was significantly increased when compared with the diabetic untreated group. The in vitro addition of vardenafil significantly enhanced SNP and EFS-induced CSMR in cavernosal tissue taken from diabetic animals given vardenafil in vivo. CONCLUSIONS: The present findings suggest that the combination of in vitro and in vivo vardenafil enhance diabetic CSMR, reinforcing the use of vardenafil for the treatment of diabetes-induced ED.

Purinergic modulation of human corpus cavernosum relaxation.

The activation of P2Y(6) receptors has been previously reported to cause vascular smooth muscle constriction and relaxation. The aim of our study was to determine the effect of P2Y(6) receptor subtype activation on human cavernosal function. Cavernosal tissue was obtained from 23 patients undergoing gender reassignment surgery. Immunohistochemistry (IHC) and Western blotting were used to determine the presence of P2Y(6) receptors in corpus cavernosal tissue. The effects of UDP (a selective P2Y(6) receptor agonist) before and after the addition of distilled water (control), cibacron blue 3GA (CB, a P2Y(6) receptor antagonist; 10(-4) m) or N-nitro-L-arginine methyl esther (L-NAME, a NO synthase inhibitor; 10(-4) m) were assessed on phenylephrine (PE; 10(-4) m) pre-contracted cavernosal strips using organ baths. Electrical field stimulation (EFS; 0.5-32 Hz) was performed in the absence and presence of CB to determine neuronal-mediated P2Y(6) receptor responses. IHC and Western blotting revealed the presence of P2Y(6) receptors on cavernosal sections. UDP at 10(-4) m and 10(-3) m induced a 5% and 16% relaxation of the PE-mediated response (both p < 0.0001), respectively, which was significantly blocked by CB (48% reduction of the UDP 10(-3) m response, p < 0.002) but not affected by L-NAME. EFS-induced relaxations of pre-contraction strips were not significantly altered by CB. We have found the presence of P2Y(6) receptors in human cavernosal tissues, that when activated induce cavernosal smooth muscle cell relaxation via non-neuronal and non-nitric oxide dependent mechanism. Further investigation is needed to establish whether P2Y(6) receptors play a physiological role in penile erection.

Changes in cholinergic and purinergic neurotransmission in the diabetic rabbit bladder.

BACKGROUND: Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes in autonomic receptors and alterations in detrusor structure and function. The changes in cholinergic and purinergic neurotransmission in the DM rabbit bladder were evaluated. MATERIALS AND METHODS: DM was induced with alloxan in adult male New Zealand White rabbits. At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in organ baths. Transmural electrical field stimulation (EFS: supramaximal voltage, 0.1 ms duration, 10 s trains) was performed in the presence of atropine (10(-6) M) or alpha, beta-methylene ATP (10(-6) M), and after adding tetrodotoxin10(-6) M. Purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components were calculated independently and compared with those from controls. RESULTS: Both normal and DM detrusor and bladder neck strips contracted in a frequency-dependent fashion in response to transmural EFS. A plot of EFS vs. detrusor contractility showed a decrease (ANOVA < 0.001) in the cholinergic nerve-mediated component, whereas the purinergic nerve-mediated component was increased (ANOVA < 0.001) in the DM detrusor compared to the control. The total EFS- and KCl-induced responses were unaltered in the DM group compared to the controls. There was no difference in purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components in strips from the bladder neck for both normal and DM rabbits. CONCLUSION: These results suggest that an enhancement of purinergic and a reduction of cholinergic neurotransmission occur in the detrusor muscle of the diabetic rabbit. These changes may contribute to the pathophysiology of diabetic cystopathy.

Activity of high-dose toremifene plus cisplatin in platinum-treated non-small-cell lung cancer: a phase II California Cancer Consortium Trial.

PURPOSE: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. MATERIALS AND METHODS: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. RESULTS: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. CONCLUSION: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.

Integration of new chemotherapeutic agents into chemoradiotherapy for stage III non--small cell lung cancer: focus on docetaxel.

Randomized clinical trials have shown that combinations of chemotherapy plus thoracic radiation improve survival compared with radiotherapy alone in stage III non--small cell lung cancer (NSCLC). Furthermore, two recent studies have concluded that concurrent chemoradiotherapy produces superior results to sequential administration. Dependent on the dose and schedule used, chemotherapy may contribute by eradicating distant micrometastases by improving local control as a radiosensitizer, or through both mechanisms. In general, sequential approaches in which full-dose platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by impacting distant metastases. In contrast, concurrent chemoradiotherapy using low-dose cisplatin is reported to improve survival by reducing local recurrence without an impact on distant failure rates. In view of these observations, chemoradiotherapy strategies integrating both radiosensitizing agents and dose levels of chemotherapy effective against micrometastases may prove to be most efficacious. Because distant metastases remain the major site of failure, it also is likely that more effective chemotherapy will be required to further improve the current level of response and survival. Fortunately, several newly available chemotherapeutic agents are both highly active against NSCLC and are potent radiosensitizers. In this report we review recent data regarding integration of new chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC, focusing on trials investigating docetaxel. Encouraging results, including those of the Southwest Oncology Group trial 9504, suggest that docetaxel will play a major role in the future of combined-modality therapy for locally advanced NSCLC. Semin Oncol 28 (suppl 9):26-32.

Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel.

BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.

KT3.2 and KT3.3, two novel human two-pore K(+) channels closely related to TASK-1.

We report the cloning of human KT3.2 and KT3.3 new members of the two-pore K(+) channel (KT) family. Based on amino acid sequence and phylogenetic analysis, KT3.2, KT3.3, and TASK-1 constitute a subfamily within the KT channel mammalian family. When Xenopus oocytes were injected with KT3.2 cRNA, the resting membrane potential was brought close to the potassium equilibrium potential. At low extracellular K(+) concentrations, two-electrode voltage-clamp recordings revealed the expression of predominantly outward currents. With high extracellular K(+) (98 mM), the current-voltage relationship exhibited weak outward rectification. Measurement of reversal potentials at different [K(+)](o) revealed a slope of 48 mV per 10-fold change in K(+) concentration as expected for a K(+)-selective channel. Unlike TASK-1, which is highly sensitive to changes of pH in the physiological range, KT3.2 currents were relatively insensitive to changes in intracellular or extracellular pH within this range due to a shift in the pH dependency of KT3.2 of 1 pH unit in the acidic direction. On the other hand, the phorbol ester phorbol 12-myristate 13-acetate (PMA), which does not affect TASK-1, produces strong inhibition of KT3.2 currents. Human KT3.2 mRNA expression was most prevalent in the cerebellum. In rat, KT3.2 is exclusively expressed in the brain, but it has a wide distribution within this organ. High levels of expression were found in the cerebellum, medulla, and thalamic nuclei. The hippocampus has a nonhomogeneous distribution, expressing at highest levels in the lateral posterior and inferior portions. Medium expression levels were found in neocortex. The KT3.2 gene is located at chromosome 8q24 1-3, and the KT3.3 gene maps to chromosome 20q13.1.

Neoadjuvant therapy for non-small cell lung cancer.

Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.

Gemcitabine in combination with new platinum compounds: an update.

Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of the nonhematologic toxicities associated with cisplatin. Although few direct comparisons have been made, when administered by area under the concentration-time curve (AUC) dosing, carboplatin is probably equivalent to cisplatin in advanced non-small-cell lung cancer and provides an improved therapeutic index. Based on its favorable toxicity profile, carboplatin has supplanted cisplatin for use in combination with paclitaxel in several different tumor types. Initial trials combining gemcitabine and carboplatin using standard days 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia was problematic. More recently, 21-day schedules in which gemcitabine is administered only on days 1 and 8 have demonstrated both efficacy and improved toxicity profiles. Here we review recent studies investigating gemcitabine plus carboplatin and preliminary data regarding combinations of gemcitabine with the new platinum analog oxaliplatin.

Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment.

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.

Gemcitabine/carboplatin combination regimens: importance of dose schedule.

Platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), in combination with a number of new chemotherapeutic agents, have demonstrated improved response or survival compared to cisplatin alone or older platinum-based regimens. Gemcitabine (Gemzar)-platinum combinations are of particular interest because of their interactive mechanisms of action, demonstrated preclinical synergism, and the single-agent activity of gemcitabine. Indeed, gemcitabine and cisplatin regimens have proven to be among the most efficacious in the palliative treatment of advanced non-small-cell lung cancer. In view of the reduced nonhematologic toxicities associated with the platinum analogue, carboplatin, several combinations of new agents and carboplatin have been developed and incorporated into clinical practice. This article describes recent clinical trials evaluating gemcitabine plus carboplatin, and the impact of the dosing schedule on the feasibility and tolerability of this combination.

Treatment of poor-prognosis extensive disease small-cell lung cancer with an all-oral regimen of etoposide and cyclophosphamide - a Southwest Oncology Group clinical and pharmacokinetic study.

PURPOSE: An all-oral regimen of etoposide and cyclophosphamide was developed for use in poor-prognosis extensive disease small-cell lung cancer. Limited pharmacokinetic sampling was used to derive a pharmacodynamic model predictive of myelosuppression early in the course of therapy. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive and had extensive disease small-cell lung cancer with either SWOG performance status 2 or serum albumin <3.5 g/dl. The first cohort (n = 18) received etoposide orally at 50 mg daily and cyclophosphamide orally at 50 mg daily days 1-14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both agents orally at 50 mg twice daily days 1-14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at 1 h, 2 h, and 23.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosuppression. RESULTS: A total of 173 treatment cycles were delivered. Patients on the daily regimen had a 22% response rate (complete and partial), a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytopenia and alopecia were the most common toxicities seen. Significant granulocytopenia could be predicted for the twice-daily regimen according to the formula ln(AGC nadir)=7.80 - 1.88(trough), with an increased incidence of granulocytopenia if the etoposide trough value was >/=1.49 microg/ml. CONCLUSION: Oral etoposide and oral cyclophosphamide given days 1-14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposide level obtained within 24 h of starting therapy can predict severe granulocytopenia.

Paclitaxel (Taxol): an inhibitor of angiogenesis in a highly vascularized transgenic breast cancer.

Paclitaxel (Taxol), a promoter of microtubule polymerization and a radiosensitizing agent, is one of the more active anticancer drugs in the current treatment of solid tumors. In this study, we show that paclitaxel possesses an antiangiogenic property associated with a down-regulation of vascular endothelial growth factor (VEGF) in a highly-vascularized transgenic murine breast cancer (Met-1). Paclitaxel, at non-cytotoxic doses of 0, 3 and 6 mg/kg/day, was administered intraperitoneally for 5 days to nude mice bearing the Met-1 breast tumor. Extent of intratumoral angiogenesis, as indicated by microvessel tortuosity and microvessel density, was significantly reduced by paclitaxel in a dose-dependent manner. Paclitaxel also suppressed expression of VEGF in the Met-1 cells transplanted in nude mice or maintained in cell culture. These results indicate that antiangiogenesis associated with a down-regulation of VEGF is an additional mode of action of paclitaxel.