Abstract: Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50–100 μM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 μM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule. Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter. The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30–74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 μM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression. Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

Abstract: Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.

Abstract: To investigate the cytotoxic and antitumor effects of the combination of the novel anticancer drug ET-743 and doxorubicin (Dx) and to determine whether any pharmacokinetic interaction occurs in sarcoma-bearing mice. The cytotoxicity of each drug and of their combinations was assessed in the rhabdomyosarcoma cell line TE-671 by a clonogenic assay, and isobologram analysis was performed to detect any synergistic, additive or antagonistic effects. The antitumor activities of each drug and of the combinations were also evaluated in nude mice transplanted subcutaneously with human TE-671 rhabdomyosarcoma and in C3H female mice injected intravenously with UV2237 M fibrosarcoma or with the Dx-resistant subline UV2237 M-ADM which overexpresses Pgp. Antitumor activity was evaluated by monitoring the TE-671 tumor volume over time and, in the case of the murine fibrosarcomas, by evaluation of lung deposits at autopsy quantified by determining lung weight. Pharmacokinetic studies were performed in TE-671-bearing mice. ET-743 was determined in plasma by an HPLC-MS method and Dx in plasma and tissue by an HPLC method with fluorescence detection. The combination of ET-743 and Dx was found to be additive with the average combination index slightly lower than 1 at all survival levels, suggesting weak synergism. In TE-671 tumors in vivo the activity of ET-743 or Dx given alone was marginal, whereas the combination produced a significant antitumor effect. The log cell kill (LCK) values were 0.13 and 0.33 for ET-743 and Dx alone, whereas they ranged from 0.85 to 1.12 for the combination. Giving ET-743 1 h before Dx slightly enhanced the effect (LCK 1.12) compared with giving the drugs simultaneously (LCK 0.85) or in the opposite sequence (LCK 0.92). In UV2237 M fibrosarcoma, both Dx and ET-743 showed an effect in reducing the weight of lung metastases, although the combination of the two drugs was not superior to each drug alone. In UV2237 M-ADM tumors neither of the two drugs was active, whereas the combination, particularly when the two drugs were given simultaneously, produced a significant effect. Plasma levels of ET-743 and Dx were not significantly different when the drugs were given alone or in combination. The concentrations of Dx in tissues including tumor, liver, heart and kidney were found to be the same whether the drug was given alone or in combination with ET-743. These results indicate that ET-743 and Dx in combination produce an additive effect against human sarcoma cells, reinforcing the idea that they act by a different mechanism of action. In mice no pharmacokinetic interaction between the two drugs was found. The observed activity in UV2237 M-ADM and in human TE-671 sarcoma suggests that the combination of the two drugs could be effective for tumors displaying low sensitivity to each drug given alone. Based on these findings a phase I study on the combination of the two drugs was recently initiated.

Abstract: To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy (P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6±6.188% versus 22.6±3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum.

Abstract: More than 90% of gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT, and activating mutations of the KIT gene are detectable in the vast majority of these tumors. Imatinib mesylate (formerly STI571) is a potent inhibitor of KIT kinase activity and has been proven to be highly active in patients with unresectable or metastatic GIST expressing immunohistochemically detectable KIT protein. Here we report a patient with metastatic GIST who responded well to imatinib mesylate treatment despite the near absence of KIT expression in two different samples of his tumor. The tumor was morphologically typical for a GIST, stained positively for CD34, and harbored an in-frame deletion (WK 557–558) in KIT exon 11 that is common in GISTs. Our experience with this patient suggests that even GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy.

Abstract: Purpose. Previous studies have shown that angiotensin peptides stimulate the proliferation of hematopoietic progenitors in vitro, promote survival after exposure to lethal irradiation as well as accelerate the recovery of white blood cells (WBC), i.e., lymphocytes, monocytes and neutrophils, and platelets. These changes in the level of formed elements in the blood after irradiation was thought to be due to increases in the numbers of bone marrow progenitors including myeloid, erythroid and megakaryocyte progenitors by the action of angiotensin peptides. In view of these findings, the effect of angiotensin peptides on recovery after chemotherapy was assessed. Materials and methods. The effect of angiotensin II (AII) and angiotensin(1–7) (A1–7) on the recovery of WBC and platelets in the blood, as well as the number of myeloid, erythroid and megakaryocyte progenitors in the bone marrow and the number of myeloid progenitors in the blood after intravenous administration of chemotherapeutic drugs was assessed in a mouse model. Results. In initial studies, subcutaneous administration of 10 or 100 µg/kg per day of AII starting either 2 days before or 2 days after intravenous administration of 5-fluorouracil (5FU) accelerated WBC recovery (return to baseline between 7 and 14 days). Further, consistent with previous observations, the number of myeloid progenitors in the bone marrow and blood was increased after systemic administration of angiotensin peptides. The comparability of A(1–7) and AII in their effect on hematopoietic recovery after chemotherapy was shown in subsequent studies. Daily administration of both AII and A(1–7) increased platelet numbers in the peripheral blood and myeloid, erythroid and megakaryocyte progenitors in the bone marrow. As 5FU is not a stem cell toxin, these studies were repeated with administration of A(1–7) initiated before or after intravenous cyclophosphamide. Following treatment with A(1–7) before cyclophosphamide the numbers of circulating WBC initially increased and then decreased starting on day 14. Following treatment with A(1–7) 2 days after cyclophosphamide the numbers of WBC and the numbers of myeloid progenitors increased in the peripheral blood and bone marrow. Conclusions. These findings suggest that angiotensin peptides accelerate hematopoietic recovery in multiple cellular lineages after chemotherapy, perhaps through an increase in the number of early hematopoietic progenitors.

Abstract: Purpose The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination.

Abstract: Purpose. Mylotarg has moderate activity as a single agent in patients with CD33-positive refractory or relapsed acute myelogenous leukemia (AML). A combination of an anthracycline and cytarabine (ara-C) is the core of most AML induction regimens. We conducted a pilot study of Mylotarg combined with idarubicin and ara-C in patients with refractory or relapsed AML. Methods. Mylotarg was administered at 6 mg/m2 intravenously on days 1 and 15, idarubicin 12 mg/m2 daily on days 2 through 4, and ara-C at 1.5 g/m2 daily on days 2 through 5 (MIA) Results. Of 14 patients were treated, 4 (29%) had primary resistant AML, and 10 (71%) relapsed AML. The median age of the patients was 61 years (range 34–74 years). MIA induced complete remission (CR) in three patients (21%) and CR with incomplete platelet recovery (CRp) in three patients (21%). The median survival was 8 weeks (range 2–64 weeks), and the median failure-free survival of CR patients was 27 weeks (range 11–64 weeks). All patients developed grade 3/4 myelosuppression – severe sepsis occurred in ten patients (71%). Other grade 3/4 nonhematologic toxicities included hepatic transaminitis, oral mucositis, and diarrhea. Two patients (14%) developed hepatic venoocclusive disease (VOD). Conclusions. The addition of Mylotarg to idarubicin and ara-C is feasible. MIA has significant activity in patients with refractory AML. Hepatotoxicity and VOD are significant toxicities of Mylotarg-based combinations.

Abstract: Background. The pharmacokinetics and tissue distribution of photofrin II (PF) and its efficacy in sonodynamic therapy were studied in rats bearing AH130 solid tumors. Materials and methods. In order to find the optimum timing of the ultrasound exposure after administration of PF, the PF concentrations in plasma, skin, muscle and tumor were measured and pharmacokinetically analyzed. Antitumor effects were estimated by measuring tumor size. Results. Since the highest concentration of PF in tumors occurred 24 h after administration, ultrasound administration 24 h after the intravenous administration of PF was chosen. Ultrasound alone showed a slight antitumor effect, which became increasingly significant as the dose of PF was increased, while PF alone showed no significant effect. Conclusions. PF significantly sensitized solid tumors to the antitumor effect of ultrasound in a synergistic manner.

Abstract: Purpose Clinical studies indicate that anthracycline cardiotoxicity increases with patient age. This may be due to altered pharmacokinetics or pharmacodynamics. A parameter termed 'early clearance' has been shown to decrease with age in patients receiving intravenous doxorubicin. This parameter, as defined, has no immediate relationship to any physiologically based pharmacokinetic parameter. We therefore reevaluated the pharmacokinetic data to better define the relationship between doxorubicin disposition and patient age.

Abstract: Perillyl alcohol is a plant-derived lipid with preclinical antitumor activity. Its proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including the proto-oncogene p21-ras, thereby blocking signal transduction. This phase I trial was conducted to determine the optimal dose of perillyl alcohol. The study group comprised 21 adults with advanced solid tumors who were treated with perillyl alcohol, delivered orally, four times daily, without interruption. Doses ranged from 4,800 to 11,200 mg/m2 per day. The maximum tolerated dose (MTD) for this schedule was determined to be 8400 mg/m2 per day. The dose-limiting toxicities in this trial were nausea and vomiting, encountered in all patients at the highest dose level. No antitumor activity was observed. Pharmacokinetic data suggest dose-dependent increases in Cmax of perillic acid, a metabolite of perillyl alcohol, but with high inter- and intrapatient variability. The MTD of perillyl alcohol for this schedule was determined to be 8400 mg/m2 per day. This is higher than the MTDs determined in other similar phase I trials. This may have been due to the fact that the gastrointestinal symptoms caused by perillyl alcohol are highly subjective, with high interpatient variability. Phase II trials of perillyl alcohol in hormone-refractory prostate, breast, ovarian and colorectal cancer using doses in the range 4800–6400 mg/m2 per day are underway.

Abstract: Purpose. To evaluate and compare the ototoxicity and nephrotoxicity of cisplatin and cis-diammineaquachloroplatinum(II) ion (monohydrated complex of cisplatin, MHC, formed in vivo by hydrolysis of cisplatin) after their separate administration to guinea pigs. Methods. A dose of 4 mg/kg body weight of MHC was deemed suitable for the toxicity evaluation after dose titration. Electrophysiological hearing thresholds (auditory brainstem response, ABR), plasma creatinine and weight were measured in three groups of animals before and after receiving MHC 4 mg/kg (0.0141 mmol/kg), cisplatin 4.24 mg/kg (0.0141 mmol/kg, i.e. equimolar dose) or cisplatin 8 mg/kg (0.0267 mmol/kg) as an i.v. bolus injection. Cisplatin and MHC were analysed using liquid chromatography with post-column derivatization. Results. Administration of MHC 4 mg/kg caused a moderate ABR threshold shift, a significant increase in creatinine and a significant weight loss, changes similar to those seen after administration of cisplatin 8 mg/kg. Animals given cisplatin 4.24 mg/kg had a slight increase in creatinine, but had no ABR threshold shift and gained weight during the experiment. The pharmacokinetic parameters of cisplatin and MHC were estimated after administration of cisplatin 4.24 mg/kg and MHC 4 mg/kg. The area under the blood-ultrafiltrate concentration versus time curve (AUC) for cisplatin after administration of MHC 4 mg/kg was 23% (56±5.0 µg·min·ml–1) (means±SD) of that after administration of cisplatin 4.24 mg/kg (240±25 µg·min·ml–1). The AUC for MHC after administration of cisplatin 4.24 mg/kg was 20% (30±4.9 µg·min·ml–1) of that after administration of MHC 4 mg/kg (149±26 µg·min·ml–1). Conclusions. MHC 4 mg/kg causes ototoxicity, nephrotoxicity and weight loss when administered to guinea pigs. The toxic effects were similar to those seen after administration of cisplatin 8 mg/kg and higher than those seen after administration of cisplatin 4.24 mg/kg.

Abstract: For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel infused intraperitoneally in two isotonic carrier solutions: 15% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered Rats were given a single dose of intraperitoneal paclitaxel (40 mg/m2) in 01 ml/g body weight of each carrier solution Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18 and 24 h) At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded Blood and tissues were sampled using a standardized protocol Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=00079) No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=00079), 12 h (P=00079), and 18 h (P=00317) The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=00079) and 18 h (P=00317) There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191) Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted

Abstract: Background Clinical trials of gefitinib (Iressa, ZD1839) in combination with cytotoxic agents have been carried out or are ongoing in several varieties of tumor. To provide a rationale for future clinical trials, the effects of combining gefitinib with oxaliplatin in different sequences of administration and different dose ratios in two colon cancer cell lines were evaluated.

Abstract: Purpose Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60–100 mg/m2 by infusion every 3 weeks. Now weekly low-dose (30–36 mg/m2) regimens are being evaluated in phase I trials. Such low-dose studies require a more sensitive, specific and rapid assay of docetaxel in biological fluids for the determination of pharmacokinetic parameters. Because docetaxel is primarily metabolized by CYP3A4 and is highly protein-bound in the plasma, there is potential for drug-drug interactions and high interpatient variability in pharmacokinetics. Therefore, pharmacokinetic studies are an important component to understanding the therapeutic variability of docetaxel-containing chemotherapeutic regimens.

Abstract: Anticancer drug discovery and development is a rapidly evolving field. Recent advances in molecular oncology and the effort to completely sequence the human genome has led to an explosion in our understanding of the mechanisms involved in the transformation and growth of malignant cells. This in turn has led to major changes in our approach to traditional drug discovery and development. A dynamic example of how genomics is affecting cancer developmental therapeutics is provided by the ongoing changes being implemented in the anticancer drug development program run by the US National Cancer Institute (NCI). This review summarizes the history of drug screening and development efforts at the NCI over the past five decades from its inception up to its current state emphasizing molecularly targeted therapies. These changes have not only had an impact on drug discovery, but they are also providing new paradigms for the design and conduct of preclinical and early clinical trials.

Abstract: The induction of polyamine catabolism has been directly associated with the cytotoxic response of various tumor types to the antitumor polyamine analogues. Initially, human polyamine catabolism was assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO). We have recently cloned a new polyamine analogue-inducible human polyamine oxidase (PAOh1/SMO) that efficiently uses spermine as a substrate. The induction of PAOh1/SMO in response to multiple polyamine analogues was examined in representative lung tumor cell lines. Representatives of three different classes of antitumor polyamine analogues were examined for their ability to induce PAOh1/SMO. The human adenocarcinoma line, NCI A549 was found to be the most responsive line with respect to induction of PAOh1/SMO in response to analogue exposure. Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines. Using a series of polyamine analogues, it was found that the most potent inducers of PAOh1/SMO possessed multiple three-carbon linkers between nitrogens, as typified by N1,N11-bis(ethyl)norspermine. Since PAOh1/SMO is an analogue-inducible enzyme that produces H2O2 as a metabolic product, it may play a significant role in determining the sensitivity of various human tumors to specific polyamine analogues.

Abstract: The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers. A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg·h/l·m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC ≤5, by 100% for AUC >5–10, by 50% for AUC >10–15, and by 25% for AUC >15–20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program. Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5–1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23–50%) in the intention-to-treat population and 47% (95% CI 29–65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient). This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.

Abstract: Purpose In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis.

Abstract: Purpose We have previously demonstrated doxorubicin-induced urokinase (uPA) and interleukin-8 (IL-8) expression in human H69 small-cell lung carcinoma (SCLC) cells by a microarray technique using Human Cancer Chip version 2, in which 425 human "cancer-related" genes are spotted on the plates. The microarray analysis also revealed a significant induction of tumor necrosis factor-alpha (TNF-α), and doxorubicin-induced macrophage chemoattractant protein-1 (MCP-1) expression was demonstrated by an RNase protection assay. We extended the study by testing the effects of doxorubicin on the induction of TNF-α, uPA, IL-8 and MCP-1 in other types of lung carcinoma cells.

Abstract: PURPOSE: MAG-camptothecin (MAG-CPT) is the lead compound of a novel drug delivery system in which an active cytotoxic moiety, camptothecin (CPT), is covalently linked to a soluble polymeric carrier ...

Abstract: Purpose. Interferon-alpha (IFN-alpha) has been shown to control symptoms, reduce platelet counts, and reduce the bone marrow megakaryocyte mass in patients with essential thrombocythemia (ET). A semisynthetic protein-polymer conjugate of IFN-alpha 2b (PEG-IFN2b) increases the serum half-life of IFN-alpha 2b. We conducted a pilot study of Peg-IFN2b in patients with ET. Patients and methods Patients with a history of persistent (greater than 2 months) platelet counts >600×109/l, with hyperplasia of bone marrow megakaryocytes in the absence of an alternate identifiable cause of thrombocytosis were eligible. Patients were required to have either thrombohemorrhagic signs and/or symptoms if previously untreated; persistence of thrombohemorrhagic signs and/or symptoms if receiving anagrelide, IFN-alpha, or hydroxyurea; or intolerance to anagrelide, IFN-alpha, or hydroxyurea. The initial PEG-IFN2b dose was from 1.5 to 4.5 µg/kg per week subcutaneously with subsequent dose adjustments as indicated by response and adverse events. Results. Eleven patients (nine female, median age 54 years, range 26–69 years) were treated. PEG-IFN2b rapidly controlled platelet counts and resolved symptoms in all patients. The median duration of PEG-IFN2b therapy on-study was 9 months (range 4–17 months). No patient had signs or symptoms of thrombosis or hemorrhage while on study. After 2 months of therapy, 10 patients (91%) were in complete remission , and 11 (100%) after 4 months. One patient discontinued therapy at 4 months because of persistent grade 3 fatigue and a second at 5 months because of anxiety and depression. Conclusion. PEG-IFN2b has significant activity in patients with ET. Long-term follow-up of a larger cohort of patients is needed to define its role in this disease.

Abstract: To demonstrate that arsenic trioxide (As2O3) induces apoptosis via a mitochondrial pathway in both parent T lymphoblastoid leukemia MOLT-4 cells and cells of its daunorubicin-resistant subline, MOLT-4/DNR, expressing functional P-gp. Cell growth was measured using an MTT assay. Cell viability was determined using a dye exclusion test. Intracellular glutathione (GSH) was measured using a glutathione assay kit. Mitochondrial membrane potential (MMP) was assessed by rhodamine 123 (Rh123) staining intensity on flow cytometry. Caspase-3 activity was evaluated using a commercially available assay kit on flow cytometry. The percentage of cells undergoing apoptosis was estimated in terms of caspase+/PI− cells on flow cytometry after assessment for activation of caspase-3 by adding PI. MOLT-4 cells and MOLT-4/DNR cells were similarly sensitive to the apoptosis-inducing effect of As2O3. Buthionine sulfoxide (BSO) and ascorbic acid (AA) rendered these cells more sensitive to As2O3, whereas N-acetylcysteine (NAC) reduced this sensitivity. BSO and AA decreased, but NAC increased, the intracellular GSH contents of both MOLT-4 and MOLT-4/DNR cells. Decreasing GSH with BSO potentiated As2O3-mediated growth inhibition, disruption of MMP, activation of caspase-3 and apoptosis of cells. Clinically relevant doses of AA enhanced the anticancer effects of As2O3 via the disruption of MMP, activation of caspase-3, and induction of apoptosis. In contrast, increase GSH levels with NAC attenuated all of these As2O3-mediated actions. The sensitivity of MOLT-4 and MOLT-4/DNR cells to As2O3 was associated with the intracellular GSH content. As2O3 induced apoptosis in parent MOLT-4 cells and MOLT-4/DNR cells expressing functional P-gp via depletion of intracellular GSH, and subsequent disruption of MMP and activation of caspase-3.

Abstract: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors. We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m2 per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling. The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), Cmax 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 μg/ml·h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and Cmax (P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies. This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.