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Background After promising preclinical studies using a thoracoscopic regional lung chemotherapy technique less morbid than open perfusion methods, we initiated a Phase I clinical study. Methods Four performance status 0 to 1 patients with oligometastatic stage IV lung cancer underwent unilateral thoracoscopic lung suffusion targeting the bulk of primary disease and regional lymph nodes. We used the term suffusion (permeation of an organ) to describe the total lung distribution of chemotherapy afforded by venous distention akin to retrograde cardioplegia physiology. This was obtained by temporary thoracoscopic pulmonary vein occlusions and fluoroscopy-guided transfemoral intravascular balloon occlusion, drainage, and cisplatin distention of the main pulmonary artery. Single-lung ventilation allowed atelectasis that helped to drain the blood under pulmonary artery occlusion, then cisplatin (5% systemic dose) was instilled during venous occlusion and lung reexpansion. Chemotherapy dwelled for 30 minutes before lung reperfusion. Results All four suffusions were successful (three right, one left). Cisplatin remained concentrated in the pulmonary circulation by the end of the dwell (1,124 versus 236 ng/mL systemic). There were no changes in the postsuffusion pulmonary function tests or lung perfusion scans. All patients were discharged early (24 to 48 hours) without chest tubes, began standard chemotherapy without delay, and completed follow-up. After two systemic chemotherapeutic cycles primary tumors had volume reductions of 96%, 88%, 64%, and 14%, with the latter showing a 100% volume increase in a nonsuffused osseous metastasis. Conclusions Our initial clinical experience of thoracoscopic lung suffusion suggests that this approach is safe and merits future study with higher dose levels.

Purpose: To determine the maximal tolerated dose of capecitabine with oxaliplatin + radiotherapy in a phase I study of localized esophageal cancer. Patients and Methods: Oxaliplatin (85 mg/m2) administered on days 1, 15, and 29. Capecitabine administered twice daily 5 days weekly; dose levels (DL) were 1, 1000; 2, 1250; and 3, 1500 mg/m2 with 50.4 Gy radiation. Results: Dose-limiting toxicity was reached at DL 3. Carboxylesterase expression in day 2 tumor specimens and induction correlated with response (p ≤ 0.05). Conclusion: The maximal tolerated dose was 85 mg/m2 of oxaliplatin, 1,250 mg/m2/day of capecitabine, and 50.4 Gy of radiation.

This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human FaDu and A253 tumors were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan in the treatment of human squamous cells carcinoma of the head and neck xenografts (FaDu and A253). Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/d x 28. The highest plasma Se concentration was achieved 1 h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Intratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.

A single cell clonal sub-line A2780/C10B that is 18-fold resistant to oxaliplatin and approximately threefold cross-resistant to cisplatin and exhibiting a metastasis associated cellular phenotype was characterized for mechanisms of resistance. The cell line exhibited a 50% reduction in the accumulation of both oxaliplatin and cisplatin relative to the parent line, while extensive decline in Pt-DNA adduct levels occurred only following oxaliplatin treatment. The basal GSH levels were fivefold higher in A2780/C10B compared to A2780 and had a fivefold elevation in gamma-GT suggesting this may be the mechanism involved in GSH elevation. The basal levels of ERCC-1, XPA and MRP-2 mRNA levels in A2780/C10B were not higher than those in A2780. The highly reduced Pt-DNA adduct formation only for oxaliplatin, but not cisplatin may be a reflection of the fact that at equimolar concentrations oxaliplatin makes fewer Pt-DNA adducts than cisplatin. The data indicate that multiple lesions occur in a single cell to produce the resistant phenotype.

Purpose: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. Methods and Materials: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly × 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction × 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. Results: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m 2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m 2 /week) had a dose-limiting diarrhea. One of 6 patients at DL (−)1 (capecitabine 725 mg/m 2 p.o., b.i.d.; oxaliplatin 50 mg/m 2 /week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). Conclusions: Capecitabine 725 mg/m 2 p.o., twice daily in combination with oxaliplatin 50 mg/m 2 /week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

In this report, electrospray ionization tandem mass spectrometry (ESI-MS/MS) for a pharmacokinetic study of IDN 5390, a novel C-seco taxane derivative, which is under preclinical evaluation, has been investigated. Our results showed that IDN 5390 and other taxanes including paclitaxel and IDN 5109 could ionize well in not only positive-, but also in negative-ion mode. Under collision-induced dissociation (CID) conditions, these compounds could fragment into similar M- (molecular), T- (taxane ring) and S- (side chain) series ions. In positive-ion ESI, the formation of both T- and S-series ions involved the breaking of the C-13 ester bond. In negative-ion ESI, however, while the formation mechanism of S-series ions remained the same, the breaking of the C-1' carboxylic ester bond resulted in T-series ions. At optimum collision energy (CE) values, M-, T- and S-series ions of IDN 5390 in both positive- and negative-ion ESI-MS/MS spectra had good intensity. This phenomenon makes both positive- and negative-ion ESI-MS/MS good methods for IDN 5390 metabolite structural characterization, i.e. to reveal the location of modification groups in IDN 5390 metabolites versus IDN 5390 either on the side chain or the taxane ring. A liquid chromatography (LC)/ESI-MS/MS method using the multiple-reaction monitoring (MRM) technique was thereafter developed to quantify IDN 5390 in dog plasma using paclitaxel as internal standard. The method was validated using a concentration range between 5 and 1000 ng/mL and had a limit of detection of 1 ng/mL. The inter-day %CV (%coefficient of variation) of the calibration standards ranged between 4.36 and 9.64%, the intra-day %CV of the calibration standards between 0.61 and 13.44%, and the mean % accuracy of the quality control samples at the low, middle and high end of the concentration curves were 12.5, 6.8 and 9.6%, respectively.

Cellular glutathione (GSH) levels are related to the resistance of tumor cells to platinum and alkylating agents, and depletion of GSH may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were evaluated in 22 patients as part of a Phase I study. Escalating doses of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mg x min/mL. Plasma samples were collected and assayed by reverse-phase high-performance liquid chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one-compartment pharmacokinetic model was fit to the mesna plasma concentrations, using M.A.P. Bayesian estimation (ADAPT II). Pharmacodynamics were evaluated by fitting an inhibitory Emax model to the cysteine concentration data. Both the pharmacokinetic (median R2 = 0.95; range = 0.85-0.98) and pharmacodynamic (median R2 = 0.96; range = 0.74-1.0) models fit the data well. Mean (coefficient of variation [CV%]) mesna pharmacokinetic parameter estimates were as follows: Vss of 15.3 (29) L/m2, CL of 4.6 (29) L/h/m2, and half-life of 2.2 (37) hours. Mean (CV%) pharmacodynamic parameter estimates were as follows: Emax of 31.7 (19) microg/mL and EC50 of 10.3 (52) microg/mL. Mesna produced a rapid, concentration-dependent reduction in plasma cysteine concentrations that could be adequately characterized by an inhibitory Emax pharmacodynamic model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two agents. Further increases in mesna doses beyond those administered in this study would be unlikely to provide additional benefit.

PURPOSE Etoposide has schedule-dependent cytotoxic activity, and clinical resistance may be overcome with prolonged low-dose therapy. Oral bioavailability is variable, and protracted intravenous administration is limited by water insolubility, which requires large infusion volumes. Etoposide phosphate (EP) is a water-soluble prodrug that is rapidly converted in vivo to etoposide, and may be administered in concentrated solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protracted venous infusion in the ambulatory setting. METHODS Twenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatory pumps for 6 weeks followed by a 2-week rest. Cohorts were treated with EP at 10, 20, 25, and 30 mg/m2/d. Steady-state plasma etoposide levels (Css) and stability of EP in infusion pumps were measured using high performance liquid chromatography (HPLC). RESULTS Myelosuppression, mucositis, and fatigue were dose-limiting. The maximum-tolerated dose (MTD) of EP was 20 mg/m2/d. The mean Css (+/- SD) of etoposide were 0.67 +/- 0.25, 1.14 +/- 0.24, 1.38 +/- 0.64, and 2.19 +/- 0.52 microg/mL at daily EP doses of 10, 20, 25, and 30 mg/m2, respectively. Neutropenia correlated with Css (r = 0.65, P = .008). EP was stable in infusion pumps for at least 7 days. Partial responses were observed in patients with hepatoma and non-small-cell lung cancer (one each). CONCLUSION EP may be conveniently and safely administered as a low-volume protracted venous infusion in the ambulatory setting. Cytotoxic plasma concentrations of etoposide are obtained at the MTD. The pharmacodynamic relationships observed suggest the possibility of pharmacologically based dosing of EP.

2574 Background: SLM reduces Iri toxicity in xenograft models at associated selenium (Se) concentrations (Con) = 15μM. We conducted a phase I clinical trial of a fixed dose Iri with escalating doses of SLM in order to identify the highest safe dose of SLM that achieves and maintains Se Conc > 15μM. Methods: A standard 3–3 escalation was conducted. Iri was given at 125mg/m2/week x 4 weeks every 6 weeks. SLM was started 1 week prior to 1st dose of Iri. A loading BID dose of SLM was given for 1 week, followed by a daily maintenance dose. Selenium trough levels were obtained on days 8 and 29 of the study (days 1 and 22 irinotecan) and once every 6 week-cycle. Seven dose-levels of SLM were investigated (loading/maintenance, in mcg): 3,200/2,800, 3,200/3,200, 4,000/3,200, 4,000/4,000, 4,800/4,800, 5,600/5,600, and 7,200/7,200. Results: 31 patients enrolled on this study: age (median 57, range 21–80), Male/Female 21/10, ECOG 0/1 (15/16), 31 with prior chemotherapy, 12 with prior radiation, 22 colorectal and 9 mixed solids. Dose escalation was successful up to dose level 7 (7,200mcg SLM PO BID × 1 week followed by 7,200mcg SLM PO QD), which was declared the recommended dose. 2 Dose limiting toxicities occurred on study: one DLT of Grade (G) 3 febrile neutropenia, G3 sepsis, G3 dehydration occurred on dose-level 1; one DLT of G3 febrile neutropenia, dehydration occurred on dose-level 7. Both DLT occurred in a setting of partial small bowel obstruction related to peritoneal carcinomatosis. Non-DLT = G3 treatment-related toxicities included: 3 G3 neutropenia (< 1 week) at DL2, 3 & 7; 2 G3 diarrhea lasting < 48 hours on DL5 & 7. A lower incidence of G2+ toxicities was noted in patients with higher Se Conc (86% for Se < 15; 67% for Se 15–20; 57% for Se> 20 μM). Toxicities related to SLM were limited to garlic-like smell to breath, sweat, and urine in few patients. Responses included 7 confirmed stable diseases and 2 confirmed partial responses. A Se Con > 15 μM was achieved at all SLM dose levels of 4,800 mcg and above. Conclusions: Doses of SLM up to 7,200 mcg BID × 7 days followed by 7,200 mcg QD can be administered safely with standard doses of Iri. Formal phase II and III studies are needed to determine if SLM reduces Iri toxicity. No significant financial relationships to disclose.

The ovarian carcinoma subline A2780/C10B (C10B) is an oxaliplatin resistant clone derived from the human ovarian carcinoma cell line A2780. The C10B cells are characterized by mesenchymal phenotype, decreased platinum uptake and increased glutathione levels (Hector et al. in Cancer Lett 245:195-204, 2007; Varma et al. in Oncol Rep 14:925-932, 2005). Na,K-ATPase-beta subunit (Na,K-beta(1)) functions as a cell-cell adhesion molecule in epithelial cells and is reduced in a variety of carcinoma cells that show mesenchymal phenotype. The purpose of this study is to evaluate the relationship between Na,K-beta expression and sensitivity to oxaliplatin.Cell lines used include A2780, C10B, C10B transfected with Na,K-beta(1) (C10B-Na,K-beta) and a canine kidney carcinoma cell line MSV-MDCK also transfected with Na,K-beta(1) (MSV-MDCK-beta subunit). Cytotoxicity studies were performed by sulforhodamine-blue assay. The Na,K-alpha(1) and Na,K-beta(1) subunit localization and expression were by immunofluorescence microscopy and Western blot analysis. Platinum accumulation measurements were by atomic absorption spectrophotometry.C10B cells express highly reduced levels of Na,K-beta(1) subunit. Exogenous expression of Na,K-beta(1) increased platinum accumulation and sensitized C10B cells to oxaliplatin. The pharmacological inhibitor of Na,K-ATPase ouabain did not alter the oxaliplatin accumulation indicating that Na,K-beta(1) sensitizes cells in a Na,K-ATPase enzyme activity independent manner. These findings were also confirmed in MSV-MDCK-beta subunit cells.This study for the first time reveals that reduced expression of the Na,K-beta(1) protein is associated with oxaliplatin resistance in cancer cells and demonstrates a novel role for this protein in sensitizing the cells to oxaliplatin. This study suggests a potentially important role for Na,K-beta(1) in both prognosis and therapy of oxaliplatin resistant malignancies.

Purpose To understand the mechanisms behind platinum drug/DENSPM-induced inhibition of cancer cell growth, we compared the effects of oxaliplatin and cisplatin when combined with DENSPM on the induction of SSAT mRNA, activity, polyamines and cell growth in A2780 human ovarian carcinoma cells and their oxaliplatin- and cisplatin-resistant variants A2780/C10B and A2780/CP, respectively. Methods Parental and Pt-resistant cells were treated with platinum agent alone, DENSPM alone or combination (10 μM each, 20 h). QRT–PCR, radioactive product measurement and HPLC were used for mRNA, activity and polyamine pools, respectively; drug interaction on cell growth was by SRB and isobologram analysis. Results Both platinum agents induced SSAT mRNA in parental A2780 cells, but not in resistant cells. Platinum drug/DENSPM combinations produced high levels of SSAT activity in parental cells with significant depletion of spermine and spermidine, but not in resistant cells. Co-treatment with platinum agents increased the levels of DENSPM in all cell lines. Oxaliplatin/DENSPM combination was superior to cisplatin/DENSPM in the inhibition of cell growth in parental cells. No synergy was observed in the resistant cells. Conclusions Increased DENSPM levels following co-treatment with Pt agents enhances the translation and stability of SSAT protein leading to polyamine pool depletion, facilitating more Pt–DNA adduct formation in parental cells. Oxaliplatin/DENSPM combination is superior to cisplatin/DENSPM in cell growth inhibition as DACH-Pt DNA adducts are cytotoxic even at relatively fewer numbers. Reduced platinum uptake in Pt-resistant cells contributes to reduced SSAT mRNA induction and absence of synergy when combined with DENSPM.