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Merrill J Egorin

Publications and source records attributed to Merrill J Egorin.

At least 55 records · Page 3Linked to original sources
PubMed2004

Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates.

PURPOSE: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. EXPERIMENTAL DESIGN: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods. RESULTS: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 microM after i.v. dosing and 0.8 to 2.8 microM after p.o. dosing. The mean +/-SD area under the plasma concentration versus time curve was 2480 +/-1340 microM.min and 1191 +/-146 microM.min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 +/-167 min after i.v. dosing and 266 +/-88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 +/-2.8 liter/kg, and the total body clearance was 12 +/-5 ml/min/kg. The mean peak CSF concentration was 0.25 +/-0.07 microM after i.v. dosing and 0.07 +/-0.04 microM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% +/-2%. CONCLUSIONS: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.

Administration, Oral↗
PubMed2004

Effect of St John's wort on imatinib mesylate pharmacokinetics.

OBJECTIVE: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity. Thus we examined the effects of St John's wort on imatinib pharmacokinetics. METHODS: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. RESULTS: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered. CONCLUSIONS: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.

Administration, Oral↗
PubMed2004

In vitro metabolism of the phosphatidylinositol 3-kinase inhibitor, wortmannin, by carbonyl reductase.

The phosphatidylinositol 3-kinase inhibitor, wortmannin, is extensively used in molecular signaling studies and has been proposed as a potential antineoplastic agent. The failure to detect wortmannin in mouse plasma after i.v. administration prompted in vitro studies of wortmannin metabolism. Wortmannin was incubated with mouse tissue homogenates, homogenate fractions, or purified, recombinant human carbonyl reductase in the presence of specified cofactors and inhibitors. Reaction products were characterized and quantified with liquid chromatography (LC)/mass spectrometry. Reaction rates were characterized using Michaelis-Menten kinetics. Wortmannin was metabolized to a material 2 atomic mass units greater than wortmannin. Liver homogenate had the highest metabolic activity. Some metabolism occurred in kidney and lung homogenates. Very little metabolism occurred in brain or red blood cell homogenates. Liver S9 fraction and cytosol metabolized wortmannin in the presence of NADPH and, to a much lesser extent, in the presence of NADH. Microsomal metabolism of wortmannin was minimal. Purified, recombinant human carbonyl reductase metabolized wortmannin. Quercetin, a carbonyl reductase inhibitor, greatly decreased wortmannin metabolism by S9, cytosol, and carbonyl reductase. The K(M) for wortmannin metabolism by purified, recombinant human carbonyl reductase was 119 +/- 9 microM, and the V(max) was 58 +/- 9 nmol/min/mg of protein. LC-tandem mass spectrometry spectra indicated that carbonyl reductase metabolized wortmannin to 17-OH-wortmannin. Wortmannin reduction by carbonyl reductase may partly explain why wortmannin is not detected in plasma after being administered to mice. Metabolism of wortmannin to 17-OH-wortmannin has mechanistic, and possibly toxicologic, implications because 17-OH-wortmannin is 10-fold more potent an inhibitor of phosphatidylinositol 3-kinase than is wortmannin.

Alcohol Oxidoreductases↗
PubMed2004

Evaluation of the OncoTCap (Oncology Thinking Cap) simulation in teaching medical students about clinical trials: some successes and some surprises.

OBJECTIVE: A training workshop for cancer clinical trials was developed utilizing a computer simulation encompassing cancer biology, metabolism, adverse effects, and clinical trial design. METHOD: Fourth-year medical students in a neoplasia elective course participated. The workshop was structured to maximize group discussions and interactions. Pretests and posttests were administered in a crossover design to evaluate learning about cancer clinical trials. Results. The comparison showed that the workshop did impart knowledge about cancer clinical trials. CONCLUSIONS: Student evaluations of the workshop showed slight improvements from the first year to the second year.

Clinical Trials as Topic↗
PubMed2004

Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

Adenocarcinoma↗
PubMed2003

Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma.

PURPOSE: SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin. METHODS: Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC(ECF)) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via (32)P-postlabeling. RESULTS: Mean+/-SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2+/-1.9, 11.9+/-3.0, and 3.5+/-0.3 microg/g, respectively. After cisplatin, mean+/-SD AUC(ECF) of unbound Pt was 0.72+/-0.46 microg/ml.h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean+/-SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1+/-3.3, 3.5+/-1.3, and 2.1+/-0.3 fmol Pt/microg DNA, respectively. CONCLUSION: This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.

Animals↗
PubMed2003

Use of high-performance liquid chromatography to characterize the rapid decomposition of wortmannin in tissue culture media.

Although wortmannin is extensively used in molecular signaling studies, its stability in tissue culture medium has not been assessed precisely. Therefore, we used high-performance liquid chromatography (HPLC) and mass spectrometry (MS) to characterize the decomposition of wortmannin in five commonly used media. Wortmannin was added to medium alone or to medium supplemented with 10% unheated or heat-inactivated fetal bovine serum and incubated at 37 degrees C. After 0, 5, 10, 20, 35, and 60 min, wortmannin remaining in the medium was quantified, and its decay constant and half-life were calculated. In all media, wortmannin decomposed monoexponentially, with half-lives between 8 and 13 min. HPLC/MS indicated that wortmannin decomposed to materials with m/z 447, 433, 373, and 313. Acidification of material produced by incubation of wortmannin in tissue culture medium or 1 microM NaOH converted the material with m/z 447 back to one that cochromatographed with and had an m/z (429) identical to that of wortmannin. Therefore wortmannin is much less stable in tissue culture medium than previously thought although some apparent loss of wortmannin reflects reversible, pH-dependent opening of the lactone ring of wortmannin. This rapid and complex decomposition of wortmannin argues for care being taken in how it is used in in vitro studies.

Androstadienes↗
PubMed2003

Liquid chromatographic-mass spectrometric assay for quantitation of imatinib and its main metabolite (CGP 74588) in plasma.

Imatinib mesylate (Gleevec, Glivec, STI571) is a targeted, small molecule inhibitor of the oncogenes, BCR/ABL and c-KIT, and has striking antitumor activity in patients with chronic myelogenous leukemia or gastrointestinal stromal tumors. We have developed a liquid chromatographic-electrospray ionization mass spectrometric (LC-MS) method for quantifying imatinib and its main metabolite (CGP 74588) in plasma. The assay uses deuterated imatinib as the internal standard; acetonitrile deproteination; a Phenomenex Luna C(18)(2) (5 microm, 50 x 4.6 mm) reversed-phase analytical column; a gradient mobile phase of 0.1% formic acid in methanol and water; and mass spectrometric detection using electrospray positive mode electron ionization. The assay has a lower limit of quantitation (LLOQ) of 30 ng/ml and is linear between 30 and 10000 ng/ml for both imatinib and CGP 74588. We demonstrated the suitability of this assay for imatinib using it to quantify the concentrations of imatinib and CGP 74588 in plasma of a patient given a 200-mg dose of imatinib orally. We believe that this LC-MS assay should be an important tool for future pharmacokinetic studies of imatinib.

Benzamides↗
PubMed2003

Biliary excretion of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) and metabolites by Fischer 344 rats.

PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), an analogue of the benzoquinone ansamycin geldanamycin, has been extensively studied preclinically and is being evaluated clinically. Studies were performed to define the biliary excretion of 17AAG after i.v. delivery to rats, and to characterize the metabolites of 17AAG observed in rat bile. MATERIALS AND METHODS: In vivo studies were performed in bile-duct-cannulated Fischer 344 rats given a 10 mg/kg i.v. bolus dose of 17AAG. In vitro studies were performed with cloned human CYPs and microsomal epoxide hydrolase. Biliary excretion of 17AAG and metabolites was quantified by HPLC and followed for 4 h after drug delivery. 17AAG metabolites in bile and in in vitro reaction mixtures were identified with LC/MS/MS. RESULTS: By 15 min after i.v. delivery of 17AAG, bile contained at least 15 biotransformation products with absorbance spectra similar to that of 17AAG. Of these, metabolites eluting at 2.7, 2.9, and 8.6 min were present in sufficient concentrations to be quantified, although the lack of authentic standards resulted in their being expressed as 17AAG equivalents. Within the first 4 h after drug delivery, biliary excretion accounted for 28.9+/-6.1% of the 10-mg/kg 17AAG dose. 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) accounted for 4.1+/-1.0% of the delivered dose, with 17AAG accounting for 2.0+/-0.5% and 17AG accounting for 2.1+/-0.5%. The metabolites eluting at 2.7, 2.9, and 8.6 min accounted for 10.6+/-2.0%, 9.8+/-1.2%, and 1.0+/-0.2%, respectively, of the administered dose. LC/MS/MS analysis of bile demonstrated major metabolites with molecular weights of 545 and 619, corresponding to 17AG and the diol previously described as resulting from metabolism of 17AAG by CYP3A and microsomal epoxide hydrolase. Of the remaining proposed metabolites, ten had a mass and MS/MS spectrum consistent with mono-oxygenated 17AAG metabolites. One of these metabolites has been identified as the epoxide previously described as resulting from CYP3A oxidation of the allyl double bond. Two other proposed metabolites had a mass and MS/MS spectrum consistent with demethylated 17AAG metabolites, and one had a mass and MS/MS spectrum consistent with a di-demethylated 17AAG metabolite. An analogous series of demethylated and oxidized metabolites was also observed for the 17AG metabolite. CONCLUSIONS: Biliary excretion of 17AAG represents a major route of elimination, although most of the material excreted is in the form of metabolites. Bile of rats dosed with 17AAG contained a number of metabolites not previously identified in the plasma or urine of mice treated with 17AAG, but analogous to metabolites described in bile of rats treated with 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG, NSC 707545), another geldanamycin analogue undergoing preclinical evaluation in preparation for subsequent clinical trials.

Animals↗
PubMed2003

Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B.

BACKGROUND: The Cancer and Leukemia Group B conducted a Phase II trial to evaluate the efficacy, toxicity, and pharmacokinetics of paclitaxel administered at a maximum dose density for patients with chemotherapy-naïve, advanced-stage non-small cell lung carcinoma (NSCLC). METHODS: Patients with Stage IIIB/IV or recurrent NSCLC, a performance status (PS) score of 0-1, and no history of chemotherapy exposure were eligible. Paclitaxel, 150 mg/m(2), was administered over 3 hours during Weeks 1-6 of an 8-week cycle. Doses were modified for ANC < 1500/microL or for >or= Grade 2 neuropathy on the day of therapy. Treatment continued until toxicity or disease progression. Pharmacokinetics were assessed at Weeks 1, 3, and 5 of Cycle 1. RESULTS: Thirty-eight patients (median age, 64 years; range, 31-81 years) were treated. There were 21 males (PS = 0 for 17). Eleven patients had received previous radiation, 2 had brain metastases, 25 had adenocarcinoma, 23 had Stage IV disease, 6 had StageIIIB disease, and 9 had recurrent disease. Grade 3-4 granulocytopenia occurred in 39% of patients. There were no deaths due to toxicity. Grade 2 or 3 neuropathy occurred in 29% and 24% of patients, respectively. Ten (27%) patients had Grade 3 hyperglycemia (glucose concentration > 250 mg/dL). There were 16 partial responses (42%; 95% confidence interval [CI], 26-59%). The median survival period was 12.3 months (95% CI, 7.9-19.6%), and the 1-year and 2-year survival rates were 52% (95% CI, 39-71%) and 26% (95% CI, 15-45%), respectively. Paclitaxel pharmacokinetics were consistent with published values and clearance was not induced. Older age and hyperglycemia were associated with greater neurotoxicity. CONCLUSIONS: Paclitaxel at 150 mg/m(2) per week x 6 every 8 weeks can be administered safely in the cooperative group setting. These Phase II data are comparable to those associated with combination therapy. The weekly dose-dense schedule may be more active than conventional schedules.

Adult↗
PubMed2003

Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study.

PURPOSE: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. PATIENTS AND METHODS: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. RESULTS: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (< or = 1 microg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses > or = 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. CONCLUSION: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.

Administration, Intravesical↗
PubMed2003

Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance.

Cisplatin is a potent cytotoxic agent that functions as a bivalent electrophile, forming both interstrand and intrastrand DNA cross-links. Cisplatin-mediated DNA damage results in cell cycle arrest and initiation of apoptotic cell death. Increased cellular glutathione concentrations have been closely correlated with cisplatin resistance but do not reduce the extent of cisplatin-DNA adduct formation. One hypothesis to explain the ability of glutathione to inhibit cisplatin cytotoxicity is that glutathione, through its antioxidant function, plays a role in apoptotic regulatory pathways. We tested this hypothesis using MCF-7 breast cancer cells transfected with the apoptotic inhibitor Bcl-2. Bcl-2 overexpression in MCF-7 cells was associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after cisplatin exposure. Treatment of MCF-7 lines with buthionine sulfoximine, an inhibitor of glutathione synthesis, normalized glutathione levels in Bcl-2 and control transfectants and completely abrogated Bcl-2-mediated cisplatin resistance without affecting Bcl-2 expression. Bcl-2 overexpression and up-regulation of glutathione were not associated with a change in either cisplatin-DNA adduct formation or repair over time. These results suggest that Bcl-2-mediated cisplatin resistance in MCF-7 cells is dependent on up-regulation of glutathione production, which contributes to cell survival by mechanisms independent of cisplatin inactivation or inhibition of DNA adduct formation. A similar dependence on glutathione for Bcl-2-mediated inhibition of cisplatin toxicity was confirmed in a second cell line, the lymphocytic precursor FL5.12. Taken together, these data suggest that apoptotic signaling after genotoxic exposure can be inhibited by the antioxidant activity of glutathione. Inhibition of glutathione synthesis or modulation of glutathione stores in tumors that overexpress Bcl-2 may comprise a novel anticancer strategy.

Antineoplastic Agents↗
PubMed2003

Sensitive liquid chromatography-mass spectrometry assay for quantitation of docetaxel and paclitaxel in human plasma.

We have developed a high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-MS) method for quantifying docetaxel and paclitaxel in human plasma. The assay fulfills the need for defining the lower plasma concentrations of these antineoplastic agents that result from a number of changes in how these agents are used clinically. The assay uses paclitaxel as the internal standard for docetaxel, and vice versa; solid-phase extraction; a Phenomenex Hypersil ODS (5 micrometer, 100x2 mm) reversed-phase analytical column; an isocratic mobile phase of 0.1% formic acid in methanol-water (70:30, v/v); and mass spectrometric detection using electrospray positive mode electron ionization. The assay has a lower limit of quantitation (LLOQ) of 0.3 nM and is linear between 0.3 nM and 1 microM for docetaxel. For paclitaxel, the LLOQ was 1 nM, and the assay is linear between 1 nM and 1 microM. We demonstrated the suitability of this assay for docetaxel by using it to quantify the docetaxel concentrations in plasma of a patient given 40 mg/m(2) of docetaxel and comparing those results to results produced when the same samples were assayed with an HPLC assay using absorbance detection. In a similar manner, the suitability of the assay for paclitaxel was demonstrated by using it to quantify the concentrations of paclitaxel in the plasma of a patient given 15 mg/m(2) of paclitaxel and comparing those results to results produced when the same samples were assayed with an HPLC assay using absorbance detection. The LC-MS assay, which proved superior because of its greater sensitivity and relatively short (7 min) run time, should be an important tool for future pharmacokinetic analyses of docetaxel and paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Thirty-seven patients were treated with oral calcitriol (0.5 micro g/kg) on day 1 followed by docetaxel (36 mg/m(2)) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later. RESULTS: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy. CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.

Aged↗
PubMed2003

Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice.

A whole-body physiologically-based model was developed to describe the pharmacokinetics of the ansamycin benzoquinone antibiotic 17-(allylamino)-17-demethoxygeldanamycin (17AAG) and its active metabolite 17-(amino-)-17-demethoxygeldanamycin (17AG) in blood, normal organs (lung, brain, heart, spleen, liver, kidney, skeletal muscle) and implanted human tumor xenograft in nude mice. The distribution of 17 AAG in all organs was described by diffusion-limited exchange models, while that of 17 AG was described by perfusion-limited models. The intrinsic clearances of 17AAG and 17AG in the liver were uniquely identified using local models and were estimated to be 4.93 ml/hr and 3.34 ml/hr. It was also estimated that the formation of 17AG in liver accounted for 40% of the 17AAG intrinsic clearance. The model for the distribution of both 17AAG and 17AG in the human breast cancer tumor xenograft included vascular, interstitial and intracellular compartments, which yielded the predicted cellular concentrations of 17AAG and 17AG two to three times higher than the corresponding whole tissue measurements at steady state. Estimates of the vascular-interstitial permeability surface-area product were similar for 17AAG and 17AG (0.23 ml/hr and 0.26 ml/hr). However, the interstitial to cellular transport rate of 17AG was three-fold greater than that of 17AAG, which resulted in the preferential uptake of 17AG over 17AAG in tumor. Indirect response models were developed to describe the combined action of 17AAG and 17AG on the onco-proteins Raf-1 and p185erbB2 in tumor. The half-life of endogenous protein turnover was estimated to be 22.6 hr for Raf-1 and 8.6 hr for p185erbB2, and both were comparable to corresponding values measured in vitro. A model for the molecular chaperon heat shock proteins HSP70 and HSP90 was developed based on the molecular mechanism of heat shock auto-regulation and the action of 17AAG and 17AG on these proteins. The model provided in vivo estimates of endogenous HSP70 and HSP90 turnover. In modeling pharmacokmetics and pharmacodynamics, Bayesian inference was employed to estimate the kinetic, physiological and molecular parameters when prior information was available.

Animals↗
PubMed2003

Enhancement of platinum-induced cytotoxicity by O6-benzylguanine.

O(6)-Benzylguanine (O(6)-BG), a potent inactivator of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), is presently in clinical trials combined with alkylating agents that modify the O(6) position of DNA guanine residues, i.e., 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide. Previous work demonstrated that O(6)-BG also enhances the cytotoxicity of cyclophosphamide, ifosfamide, and nitrogen mustards in Chinese hamster ovary cells. We have extended this study to include other clinically relevant agents that form interstrand and intrastrand cross-links including cisplatin and carboplatin. Pretreatment of a series of head and neck tumor cell lines (i.e., SQ20b, JSQ3, SCC25, SCC35, and SCC61), Chinese hamster ovary cells, and HT29 human colon tumor cells with O(6)-BG (100 micro M for 2 h before treatment and 2 h during treatment) resulted in a 2-fold decrease in the ED(50) of cisplatin and a concomitant increase in the percentage of cells undergoing apoptosis. The enhancement was independent of AGT activity. Similar enhancement was observed with carboplatin, but no enhancement was seen in AGT-deficient cell lines with radiation or temozolomide, demonstrating the dependence of the effect on bifunctional, cross-linking agents. Furthermore, levels of platinum on DNA after treatment with cisplatin increased 1.4-fold in SQ20b cells and 4.5-fold in JSQ3 cells immediately after treatment with O(6)-BG plus cisplatin and remained elevated for 48 h. Consistent with greater cytotoxicity and apoptosis is the approximately 2-fold higher amount of DNA damage when cells are treated with O(6)-BG plus cisplatin compared with cisplatin alone. Modulation of cisplatin therapy with O(6)-BG might improve the prognosis of patients with head and neck, ovarian, testicular, or lung cancer who are treated with this drug.

Animals↗
PubMed2002

Decreased tumor blood flow as measured by positron emission tomography in cancer patients treated with interleukin-1 and carboplatin on a phase I trial.

BACKGROUND: Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1alpha (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone. METHODS: In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with (15)O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30 micro g/kg given i.v. over 2 h. At 4 h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400 mg/m(2). Treatment was repeated every 28 days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24 h after IL-1 initiation. RESULTS: Mean measured pretreatment tumor blood flow was 1.82 ml/min per g. At 2, 4 and 24 h it was 1.35, 1.67 and 1.62 ml/min per g respectively. Tumor blood flow was significantly decreased ( P<0.008) at 2 h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2 h after initiation ( n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2 h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated. CONCLUSIONS: We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with (15)O water at 2 h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.

Adult↗