Biomedical subjects

Kenneth K Chan

Publications and source records attributed to Kenneth K Chan.

At least 37 records · Page 2Linked to original sources

PubMed2004

An API LC/MS/MS quantitation method for ansamitocin P-3 (AP3) and its preclinical pharmacokinetics.

Ansamitocin P-3 (AP3) is a potent maytansinoid antitumor agent isolated from microorganisms and mosses. In this study, a highly sensitive and specific electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for quantitation of AP3 was developed and validated. AP3 was extracted from rat plasma along with the internal standard, depsipeptide FK228 (NSC-630176, FR) with ethyl acetate. Components in the extract were separated on a 50mm x 2.1mm Betabasic C 85 microm stainless steel column by isocratic elution with 70% acetonitrile/0.9% formic acid. The liquid flow was passed through a pre-source splitter and 5% of the eluent was introduced into the API source. The components were analyzed in the multiple-reaction-monitoring (MRM) mode as the precursor/product ion pair of m/z 635.2/547.2 for AP3 and of m/z 541.5/424.0 for the internal standard FR. Linear calibration curves were obtained in the range 1-500 ng/mL using 0.2 mL rat plasma. The within-day coefficients of variation (CVs) were 12.9, 6.7, and 5.5% and the between-day CVs were 10.4, 6.5, and 6.4% (all n = 5) at 1, 10, and 200 ng/mL, respectively. A formulation based on normal saline and PEG300 was then developed and Sprague-Dawley male rats were given this formulated drug by i.v. bolus. Plasma drug concentrations were measured by this method and the pharmacokinetics were analyzed by standard techniques. Plasma concentration-time profiles were found to follow a triexponential decline and the terminal phase was nearly flat, suggesting that the drug distributed in deep tissue compartments or organs and then equilibrates slowly with the blood stream.

Animals↗

PubMed2004

Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder.

BACKGROUND: Immune-compromised individuals are at increased risk for developing aggressive Epstein-Barr virus (EBV)-associated lymphoproliferative disorders after primary EBV infection or for reactivation of a preexisting latent EBV infection. We evaluated the effect of depsipeptide, a histone deacetylase inhibitor, on EBV-positive lymphoblastoid cell lines (LCLs) and Burkitt lymphoma cell lines in a mouse model and explored its mechanism of action in vitro. METHODS: We studied EBV-transformed LCLs, which express a latent III (Lat-III) viral gene profile, as do some EBV-positive lymphoproliferative malignancies, and Burkitt lymphoma cell lines, which express a Lat-I viral gene profile. Cell lines were used to characterize depsipeptide-induced apoptosis, which was evaluated by flow cytometry. Flow cytometry, western blot analyses, and histone deacetylase inhibitors were used to investigate components of prodeath and survival pathways in vitro. We studied depsipeptide's effects on survival with a mouse xenograft model of EBV-positive human B-cell tumors (groups of 10 mice). All statistical tests were two-sided. RESULTS: Depsipeptide (5 mg/m2 of body surface area) treatment was associated with statistically significantly improved survival of mice carrying Lat-III EBV-positive LCL tumors, compared with that of control-treated mice (day 30: for depsipeptide-treated mice, 90% survival, 95% confidence interval [CI] = 73.2% to 100%; for control-treated mice, 20% survival, 95% CI = 5.79% to 69.1%; P<.001), but it was not associated with survival of mice carrying Lat-I EBV-positive Burkitt lymphoma tumors. Depsipeptide induced apoptosis in 64% of LCLs and in 14% of EBV-positive Burkitt lymphoma cells in vitro. Depsipeptide-treated LCL cultures had two distinct cell populations--one sensitive and one resistant to depsipeptide. Depsipeptide-mediated apoptosis was associated with a 12-fold increased level of active caspase 3, but some apoptosis persisted despite z-VAD-fmk treatment to inhibit caspase activity. Depsipeptide-resistant LCLs expressed higher levels of latent membrane protein 1 (LMP1; P = .017), BCL2 (P = .032), and nuclear factor kappaB (NF-kappaB) (P<.001) than depsipeptide-sensitive LCLs; this resistance was circumvented by treatment with PS-1145, an inhibitor of NF-kappaB activation (P<.001). CONCLUSIONS: Apoptosis is induced by depsipeptide via caspase-dependent and -independent pathways in Lat-III EBV-positive LCLs and is enhanced by inhibiting NF-kappaB activity. Depsipeptide as a treatment for Lat-III EBV-associated lymphoproliferative disorders should be explored further in clinical trials.

Animals↗

PubMed2004

A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia.

Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules.

Aged↗

PubMed2004

Subnanogram on-line column-switching liquid chromatographic-tandem mass spectrometric quantification method for nelfinavir and methoxyphenol metabolite M1 in rat plasma.

A new on-line, rapid and sensitive column-switch LC/MS/MS method to measure nelfinavir (NFV), an HIV-1 protease inhibitor, and its major metabolite (M1) in rat plasma was developed. Rat plasma containing the analytes and the internal standard was treated with acetonitrile and the supernatant was processed through an on-line extraction and an analytical columns, with a column-switch device. ESI-LC/MS with multiple reaction monitors for appropriate analytes was performed. This assay gave a limit of quantitation (LOQ) of <1 ng/mL for the analytes with 5 min run time. The within-run and between-run precisions were <12 and <10%, respectively. This analytical method was successfully applied to a study to correlate changes in maternal and placental NFV plasma concentrations in rats following NFV exposure in utero.

Animals↗

PubMed2004

Carotenoids/vitamin C and smoking-related bladder cancer.

Previous epidemiological studies of fruit and vegetable intake and bladder cancer risk have yielded inconsistent results, especially with respect to the role of cigarette smoking as a possible modifier of the diet-bladder cancer association. A population-based case-control study was conducted in nonAsians of Los Angeles, California, which included 1,592 bladder cancer patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and race between January 1, 1987 and April 30, 1996. Information on smoking, medical and medication history, and intake frequencies of food groups rich in preformed nitrosamines, vitamins A and C and various carotenoids, were collected through in-person, structured interviews. Beginning in January 1992, all case patients and their matched control subjects were asked for a blood sample donation at the end of the in-person interviews for measurements of 3- and 4-aminobiphenyl (ABP) hemoglobin adducts, and glutathione S-transferases M1/T1/P1 (GSTM1/T1/P1) and N-acetyltransferase-1 (NAT1) genotypes. Seven hundred seventy-one (74%) case patients and 775 (79%) control subjects consented to the blood donation requests. In addition, all case patients and matched control subjects were asked to donate an overnight urine specimen following caffeine consumption for measurements of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) phenotypes. Urine specimens were collected from 724 (69%) case patients and 689 (70%) control subjects. After adjustment for nondietary risk factors including cigarette smoking, there were strong inverse associations between bladder cancer risk and intake of dark-green vegetables [p value for linear trend (p) = 0.01], yellow-orange vegetables (p = 0.01), citrus fruits/juices (p = 0.002) and tomato products (p = 0.03). In terms of nutrients, bladder cancer risk was inversely associated with intake of both total carotenoids (p = 0.004) and vitamin C (p = 0.02). There was a close correlation (r = 0.58, p = 0.0001) between intakes of total carotenoids and vitamin C in study subjects. When both nutrients were included in a multivariate logistic regression model, only total carotenoids exhibited a residual effect that was of borderline statistical significance (p = 0.07 and p = 0.40 for total carotenoids and vitamin C, respectively). Cigarette smoking was a strong modifier of the observed dietary effects; these protective effects were confined largely to ever smokers and were stronger in current than ex-smokers. Smokers showed a statistically significant or borderline statistically significant decrease in 3- and 4-aminobiphenyl (ABP)-hemoglobin adduct level with increasing intake of carotenoids (p = 0.04 and 0.05, respectively). The protective effect of carotenoids on bladder cancer seemed to be influenced by NAT1 genotype, NAT2 phenotype and CYP1A2 phenotype; the association was mainly confined to subjects possessing the putative NAT1-rapid, NAT2-rapid and CYP1A2-rapid genotype/phenotype. The carotenoid-bladder cancer association was not affected by the GSTM1, GSTT1 and GSTP1 genotypes.

Acyltransferases↗

PubMed2004

Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.

PURPOSE: Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. DESIGN: Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae. CONCLUSIONS: Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

Animals↗

PubMed2004

Recent developments in the maytansinoid antitumor agents.

Maytansine and its congeners have been isolated from higher plants, mosses and from an Actinomycete, Actinosynnema pretiosum. Many of these compounds are antitumor agents of extraordinary potency, yet phase II clinical trials with maytansine proved disappointing. The chemistry and biology of maytansinoids has been reviewed repeatedly in the late 1970s and early 1980s; the present review covers new developments in this field during the last two decades. These include the use of maytansinoids as "warheads" in tumor-specific antibodies, preliminary metabolism studies, investigations of their biosynthesis at the biochemical and genetic level, and ecological issues related to the occurrence of such typical microbial metabolites in higher plants.

Animals↗

PubMed2003

Identification of thiols and glutathione conjugates of depsipeptide FK228 (FR901228), a novel histone protein deacetylase inhibitor, in the blood.

Four glutathione (GSH) conjugates and two thiols were detected when depsipeptide FK228, formerly FR901228, a naturally occurring potent histone deacetylase (HDAC) inhibitor, was incubated in rat or human plasma in the presence of GSH. Their structures were elucidated by the high-performance liquid chromatography/electrospray ionization multi-stage mass spectrometry (HPLC/ESI-MS(n)) technique, and in some cases confirmed by accurate mass measurement. These products were also detected in rat and human blood homogenates following their incubation with FK228, but were not detected in GSH solution alone. A possible scheme for its formation is proposed. One of the thiols has recently been found to be more active as a histone deacetylase inhibitor than the parent compound.

Animals↗

PubMed2003

Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2.

We have previously reported permanent hair dye use to be a significant risk factor for bladder cancer in US women. We also have examined N-acetyltransferase-2 (NAT2) phenotype in relation to the hair dye-bladder cancer relationship, and found that the association is principally confined to NAT2 slow acetylators. In the present study, we assessed the possible modifying effects of a series of potential arylamine-metabolizing genotypes/phenotypes (GSTM1, GSTT1, GSTP1, NAT1, NAT2, CYP1A2) on the permanent hair dye-bladder cancer association, among female participants (159 cases, 164 controls) of the Los Angeles Bladder Cancer Study. Among NAT2 slow acetylators, exclusive permanent hair dye use was associated with a 2.9-fold increased risk of bladder cancer (95% CI = 1.2-7.5). The corresponding relative risk in NAT2 rapid acetylators was 1.3 (95% CI = 0.6-2.8). Frequency- and duration-related dose-response relationships confined to NAT2 slow acetylators were all positive and statistically significant. No such associations were noted among NAT2 rapid acetylators. Among CYP1A2 'slow' individuals, exclusive permanent hair dye use was associated with a 2.5-fold increased risk of bladder cancer (95% CI = 1.04-6.1). The corresponding risk in CYP1A2 'rapid' individuals was 1.3 (95% CI = 0.6-2.7). Frequency- and duration-related dose-response relationships confined to CYP1A2 'slow' individuals were all positive and statistically significant. No such associations were noted among CYP1A2 'rapid' individuals. Among lifelong non-smoking women, individuals exhibiting the non-NAT1*10 genotype showed a statistically significant increase in bladder cancer risk associated with exclusive permanent hair dye use (OR = 6.8, 95% CI = 1.7-27.4). The comparable OR in individuals with the NAT1*10 genotype was 1.0 (95%CI = 0.2-4.3). Similarly, all frequency- and duration-related dose-response relationships confined to individuals possessing the non-NAT1*10 genotype were positive and statistically significant. On the other hand, individuals of NAT1*10 genotype exhibited no such associations.

Adult↗

PubMed2003

DNA sequence specificity for topoisomerase II poisoning by the quinoxaline anticancer drugs XK469 and CQS.

The two known antineoplastic quinoxaline topoisomerase II poisons, XK469 (NSC 697887) and CQS (chloroquinoxaline sulfonamide, NSC 339004), were compared for DNA cleavage site specificity, using purified human topoisomerase IIalpha and human topoisomerase IIbeta. The DNA cleavage intensity pattern for topoisomerase IIalpha poisoning by CQS closely resembled that of VM-26, despite the lack of any apparent common pharmacophore. In contrast, the topoisomerase IIalpha DNA cleavage intensity patterns of XK469 and CQS were very different from one another despite the similar overall structures of the two drugs. This suggests that the differences in DNA site specificity of topoisomerase II poisoning by XK469 and CQS may be caused by differences in their geometry, side chains, or electronic structure. The topoisomerase IIbeta-mediated DNA cleavage sites of CQS and XK469 were also very different from one another, adding further support to this idea. Earlier work has demonstrated that a number of specific topoisomerase II poisons show very similar patterns of DNA cleavage with either topoisomerase IIalpha or topoisomerase IIbeta, suggesting that the topoisomerase II isozymes play only a minor role in choices of DNA cleavage sites. However, both of the quinoxaline topoisomerase II poisons in this study showed distinctly different and unique DNA cleavage intensity patterns with each topoisomerase II isozyme. This indicates that topoisomerase II isozymes can play a major role in DNA cleavage site selection for some classes of topoisomerase II poisons.

Antineoplastic Agents↗

PubMed2002

Dosing sequence-dependent pharmacokinetic interaction of oxaliplatin with paclitaxel in the rat.

BACKGROUND: In a phase I clinical trial of oxaliplatin (OPT) in combination with paclitaxel (PXL), a pharmacokinetic interaction was observed when OPT was given as a 2-h i.v. infusion followed by a 1-h i.v. infusion of PXL. The purpose of this study was to use a rat model to evaluate whether the pharmacokinetic interaction between OPT and PXL is dosing sequence-dependent. METHODS: One group of rats was given OPT as a 2-h i.v. infusion followed by a 1-h i.v. infusion of PXL formulated in 50% Cremophor EL (CrEL)/50% ethanol (OPT-->fPXL), similar to the current phase I clinical protocol. In a second group of rats, the fPXL was infused first to reach a quasi-steady-state plasma level of PXL, followed by an i.v. bolus dose of OPT (CIfPXL-->OPT). In a third group of rats, fPXL was replaced with the formulation vehicle, CrEL, which was infused in the same manner as in the second group. Each combination was accompanied with a control of either OPT alone or with replacement of PXL with dextrose 5% in water (CID5W-->OPT). The total platinum (Pt) levels in plasma and plasma ultrafiltrate were measured by a validated inductively coupled plasma mass spectrometry (ICPMS) method. The protein binding, red blood cell (RBC) uptake and urinary elimination of Pt were also examined in each group of rats. RESULTS: The concentration-time profiles of plasma Pt and ultrafiltrable Pt followed triexponential decays in all groups of rats. In the rat receiving OPT-->fPXL, the terminal elimination rate constant (gamma) of plasma Pt increased, with essentially no change in the total body clearance (CL) and the AUC value, when compared to those without PXL infusion (CID5W-->OPT). The steady-state volume of distribution (V(ss)) of the ultrafiltrable Pt also showed an increase in the combination group receiving OPT-->fPXL ( P<0.01). These results were similar to those from the clinical trial, although the magnitude of change was less. However, in the CIfPXL-->OPT group, both CL and V(ss) of Pt in plasma and plasma ultrafiltrate decreased, with corresponding increases in AUCs ( P<0.01). The 24-h urinary elimination of total Pt increased in both combination groups, irrespective of the dosing sequence. No difference in protein binding of Pt was observed among the groups. There was a decrease in RBC uptake in the presence of steady-state level of fPXL, but the same was not observed in the OPT-->fPXL group. Additionally, similar results were observed with OPT in combination with CrEL alone. CONCLUSIONS: These results suggest that alterations in the pharmacokinetics of OPT by fPXL are dosing sequence-dependent and mainly caused by the formulation vehicle CrEL. It is suggested that the dosing sequence of fPXL followed by OPT would be more clinically favorable because it would prolong the residence of OPT in systemic circulation. It is further recommended that the use of other formulations of PXL without CrEL or docetaxel would avoid the complication effect of CrEL.

Animals↗

PubMed2002

Arylamine exposures and bladder cancer risk.

Occupational exposure to arylamines in industrial settings was the first known cause of bladder cancer in humans. In the United States and many developed countries, these industrial dyes have been under strict government control for decades and are believed to contribute minimally to today's population burden of bladder cancer in the West. The two other recognized, and potentially substantial sources of human exposure to arylamines are cigarette smoking and use of hair dyes. This paper reviews the latest epidemiologic findings on the relationships between smoking, hair dye use and bladder cancer risk. Results support the notion that arylamines contained in cigarette smoke and permanent hair dyes are human carcinogens. Furthermore, women may experience higher bladder cancer risk than men from comparable arylamine exposure, possibly due in part to women's higher propensity for arylamine activation relative to men.

Amines↗

PubMed2002

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

Acute Disease↗

PubMed2002

Electrospray LC-MS/MS quantitation, stability, and preliminary pharmacokinetics of bradykinin antagonist polypeptide B201 (NSC 710295) in the mouse.

B201 (NSC 710295), [SUIM-(Darg-Arg-Pro-Hyp-Gly-Igl-Ser-Digl-Oic-Arg)(2)], a third generation of bradykinin (BK) antagonist, has been found to possess high potency. We report the development of a highly sensitive electrospray LC-MS/MS assay method for the analysis of B201 in plasma for the first time, using an ion-trap mass spectrometer. Human or mouse plasma (0.2 ml) was spiked with B201 and the internal standard, substance P. The compounds were extracted with a preconditioned C-18 reversed-phase column and analyzed by LC-MS/MS. The analytes were separated on a 50 x 2 mm (i.d.) BetaBasic C8 column, using a gradient elution. The positive ion selected reaction monitor mode was used monitoring the transitions of ions at m/z 938.9(3+)-->816.0(2+) for B201 and 674.3(2+)-->665.7(2+) for substance P. Assay validation was performed, and the limit of quantitation (LOQ) for B201 was found to be 1 ng/ml for human plasma and 2.5 ng/ml for mouse plasma. The recovery was 78% for B201 and 88% for substance P. The assay was linear from 2.5 to 1500 ng/ml for mouse plasma monitored. Using a 0.2 ml plasma, the within-day CVs were 9.3% at 2.5 ng/ml, 6.5% at 100 ng/ml, and 3.8% at 1000 ng/ml for human plasma (n=6). For mouse plasma, the respective within-day CVs were 17.6, 9.6, and 6.2% (n=6). The between-day CVs for human plasma were 8.2, 10.9, and 2.4%, respectively, (n=3) and the respective values for mouse plasma were 11.9, 8.6 and 6.5% (n=6). Pharmacokinetics of B201 in the mouse was studied following i.v. administration at 5 mg/kg and found to conform to a two-compartment model with an initial half-life of 14 min and a terminal half-life of 44 h. Plasma B201 peak level was detected at microg/ml range and the levels were detectable for a least 24 h. Preliminary oral bioavailability was found to be about 1%. This method demonstrates that an ion trap mass spectrometer can be a powerful tool to quantify large peptides at low nanogram per milliliter with a non-isotopically labeled internal standard.

Animals↗

PubMed2002

Chiral high-performance liquid chromatographic analysis of the enantiomers of XK469, a new antitumor agent, in plasma and urine.

XK469 (NSC697887), (+/-)-2-[4-(7-Chloro-2-quinoxaliny)oxy]-phenoxy propionic acid, an analog of the herbicide Assure(R), which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase II beta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. A chiral high-performance liquid chromatography (HPLC) assay that utilizes Chirobiotic T column for the measurement of enantiomers of XK469 in plasma has been developed with a limit of quantitation (LOQ) of 0.2 microg/ml using a 0.2 ml plasma sample. Chloroqinoxaline sulfonamide (CQS) was used as the internal standard and the assay has been validated in rat plasma. The within-run coefficient of variations (CVs) were 5.9, 5.0, and 3.1% for the S-isomer and 8.1, 4.2, 6.4% for R(+)-XK469 at 0.2, 1, and 2 microg/ml, respectively. The between-run CVs were 10.5, 5.3, and 1.9% for S(-)- and 10.9, 6.3, and 3.6% for R(+)-XK469. Using this chiral assay, a plasma concentration time data of R(+)-,S(-)-XK469 in a Fischer 344 rat receiving i.v. dosing of S(-)XK469 at 10 mg/kg was monitored. S(-)XK469 was found to be significantly converted to the R-enantiomer in circulation even when the S-enantiomer was administered. The predominant inversion from S(-)- to R(+)-XK469 was also observed in the mouse and dog plasma. In the rat, the plasma concentration-time profiles for both isomers follow two compartmental pharmacokinetics with the t(1/2 beta) for the R-enantiomer slightly longer and the clearance of the S-enantiomer higher than the R-enantiomer.

Animals↗

PubMed2002

Pharmacokinetics of oxaliplatin (NSC 266046) alone and in combination with paclitaxel in cancer patients.

UNLABELLED: Oxaliplatin (OPT), a third-generation platinating agent, is currently being evaluated in a phase II clinical trial in head and neck cancer patients and in a phase I clinical trial in combination with paclitaxel (TXL). PURPOSE: The aim of this study was to investigate the pharmacokinetics and biological correlates of OPT alone as well as the potential pharmacokinetic interaction between OPT and TXL. METHODS: In the phase II study, OPT was given alone as a 2-h i.v. infusion at 60 mg/m(2) weekly for 4 weeks with the cycle repeated after a 2-week rest. In the concurrent phase I combination trial OPT was also given as a 2-h i.v. infusion, but followed by a 1-h i.v. infusion of TXL, weekly for 4 weeks with the cycle repeated after a 2-week rest. The clinical pharmacokinetics of OPT alone and in combination with TXL were investigated in the first cycle of each treatment protocol. The platinum levels in plasma, plasma ultrafiltrate (PUF) and urine were measured by a fully validated inductively coupled plasma mass spectrometry (ICPMS) method. RESULTS: In the ten patients receiving OPT alone, the concentration-time profiles of total platinum exhibited a biexponential decline both in plasma and in PUF. The peak levels of platinum were 2.72+/-0.41 microg/ml in plasma and 1.36+/-0.42 microg/ml in PUF at the end of the OPT infusion, and the platinum levels were still detectable at >10 ng/ml 94 h after the OPT infusion. The mean terminal t(1/2) values of total platinum in plasma and in PUF were 58.9 h and 22.8 h, respectively. The AUC of ultrafilterable platinum represented about 10% of that of the total plasma platinum. The platinum levels in the DNA fraction of peripheral white blood cells (WBC) correlated with the platinum levels in PUF ( r=0.77, P<0.01). In the phase I combination study, the dose level of OPT was escalated from 35 mg/m(2) to 60 mg/m(2). The concentration-time profiles of platinum in the combination trial also showed biexponential decay in plasma and in PUF as exhibited by OPT alone. However, the terminal elimination rate constant (beta) of total plasma platinum increased at all dose levels of OPT when combined with TXL at 45 mg/m(2) ( P<0.05). A concomitant increase in clearance (CL) of total plasma platinum was observed at the OPT dose level of 45 mg/m(2) in combination with TXL at 45 mg/m(2). No statistically significant difference in the 24-h urinary elimination of total platinum was detected between the combination groups and the single-agent group. The AUC values of total platinum in PUF were proportional to OPT doses ranging from 35 to 60 mg/m(2), whether OPT was given alone or in combination with TXL. CONCLUSIONS: OPT clearance may be enhanced by TXL when the two agents are used in combination in patients. The Pt-DNA adduct level in peripheral WBC was found to be a good indicator for oxaliplatin exposure in patients, and should be further exploited for potential tumor drug exposure.

Antineoplastic Agents↗

PubMed2002

Chiral pharmacokinetics and inversion of enantiomers of a new quinoxaline topoisomerase IIbeta poison in the rat.

XK469 (NSC 697887; (+/-)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIbeta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral high-performance liquid chromatography assay, pharmacokinetics of R(+)-, S(-)-, and (+/-)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(-)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t(1/2beta) for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t(1/2beta) for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(+)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected.

Animals↗

PubMed2002

Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.

PURPOSE: The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity. PATIENTS AND METHODS: Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m(2), and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m(2). Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method. RESULTS: Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m(2). The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (1 patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m(2)). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t(1/2alpha) and t(1/2beta) at a dose of 17.8 mg/m(2) was: 8.6 liters/m(2), 11.6 liters/h/m(2), 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249-577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells. CONCLUSION: The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m(2). The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m(2) administered on day 1 and 5 of a 21-day cycle.

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