Mucinous appendiceal adenocarcinoma presenting 5 years after appendectomy.
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Anti-Bacterial Agents↗
Biomedical subjects
Henry C Pitot
Publications and source records attributed to Henry C Pitot.
Mammary tumor induction in transgenic mice expressing an RNA-binding protein.
We have analyzed mammary tumors arising in transgenic mice expressing a novel, multifunctional RNA-binding protein. The protein, which we call the c-myc mRNA coding region instability determinant binding protein (CRD-BP), binds to c-myc, insulin-like growth factor II, and beta-actin mRNAs, and to H19 RNA. Depending on the RNA substrate, the CRD-BP affects RNA localization, translation, or stability. CRD-BP levels are high during fetal development but low or undetectable in normal adult tissues. The CRD-BP is linked to tumorigenesis, because its expression is reactivated in some adult human breast, colon, and lung tumors. These data suggest the CRD-BP is a proto-oncogene. To test this idea, the CRD-BP was expressed from the whey acidic protein (WAP) promoter in mammary epithelial cells of adult transgenic mice. The incidence of mammary tumors was 95% and 60% in two lines of WAP-CRD-BP mice with high and low relative CRD-BP expression, respectively. Some of the tumors metastasized. Nontransgenic mice did not develop mammary tumors. H19 RNA and insulin-like growth factor II mRNA were up-regulated significantly in non-neoplastic WAP-CRD-BP mammary tissue. WAP-CRD-BP mice are a novel model for mammary neoplasia and might provide insights into human breast cancer biology.
5' Untranslated Regions↗
Alterations in specific gene expression and focal neoplastic growth during spontaneous hepatocarcinogenesis in albumin-SV40 T antigen transgenic rats.
Transgenic rats containing the mouse albumin promoter and enhancer directing the expression of simian virus (SV40) T antigen (T Ag) exhibited a 100% incidence of hepatic neoplasms by 24-36 wk of age. These transgenic rats exhibited expression of large T Ag and c-myc protein within focal basophilic lesions and nodules, but not in surrounding hepatocytes. At 24 wk of age, female TG+ rats exhibited a significantly greater number of lesions and a much greater percentage of the liver occupied by TG+ focal hepatic lesions than did their male TG+ littermates. Previous studies on these animals [Sargent et al., Cancer Res 1997;57:3451-3456] demonstrate that at 12 wk of age approximately one-third of metaphases in hepatocytes exhibit a duplication of the 1q3.7-1q4.1 region of rat chromosome 1, with the smallest common region of duplication being that of 1q4.1. Duplication of the 1q3.7-1q4.3 region is also noted in many primary hepatic neoplasms resulting from the multistage model of Initiation-Promotion-Progression (IPP) [Sargent et al., Cancer Res 1996;56:2985-2991]. This region is syntenic with human 11p15.5 and mouse 7ter, which have been implicated in the development of specific neoplasms. Within the syntenic region was a cluster of imprinted genes whose expression we investigated in livers and neoplasms of TG+ rats. H19 was expressed in almost all of the neoplasms, but not in normal adult liver cells. Igf2 expression was detected in the majority of hepatic neoplasms of female TG+ rats, but in a relatively smaller number of neoplasms of TG+ males. The expression of p57Kip2 (Kip2), a cyclin-dependent kinase inhibitor that was also in the imprinted region, exhibited some variable increased expression predominantly in hepatic neoplasms from livers of female TG+ rats. Other imprinted genes within the imprinted gene cluster-insulin II (Ins2), Mash2 (which codes for a basic helix-loop-helix transcription factor), and Kvlqt1 (coding for a component of a potassium transport channel)-showed no consistently different expression from that seen in normal hepatocytes. Another gene, also located on the long arm of chromosome 1, that showed changes was the ribonucleotide reductase M1 subunit (Rrm1), in which an increase in its expression was found. This was seen in hepatic neoplasms of TG+ rats of both sexes compared with surrounding normal-appearing liver. Because hepatic neoplasms developing in livers of rats treated with chemical carcinogens commonly exhibit an increased expression of c-myc mRNA, expression of this gene was investigated in focal lesions and livers of TG+ rats, although c-myc was not located on chromosome 1. c-myc mRNA was increased in focal lesions, nodules, and neoplasms in both male and female TG+ rats compared with adult and surrounding liver. Immunostaining for c-myc protein demonstrated detectable levels in isolated single cells as well as focal lesions and neoplasms. Thus, the enhanced c-myc expression, common to all hepatic neoplasms in this system, coupled with enhanced expression of Igf2 in female TG+ rats, may be responsible for the increase in growth rate in hepatic neoplasms of female TG+ rats compared with that in livers of male TG+ rats and may contribute to neoplastic progression in the liver of this transgenic model.
Albumins↗
Changes in the DNA methylation profile of the rat H19 gene upstream region during development and transgenic hepatocarcinogenesis and its role in the imprinted transcriptional regulation of the H19 gene.
Monoallelic expression of the imprinted H19 and insulin-like growth factor-2 (Igf2) genes depends on the hypomethylation of the maternal allele and hypermethylation of the paternal allele of the H19 upstream region. Previous studies from our laboratory on liver carcinogenesis in the F1 hybrid of Fischer 344 (F344) and Sprague-Dawley Alb SV40 T Ag transgenic rat (SD) strains revealed the biallelic expression of H19 in hepatomas. We undertook a comparative study of the DNA methylation status of the upstream region of H19 in fetal, adult, and neoplastic liver. Bisulfite DNA sequencing analysis of a 3.745-kb DNA segment extending from 2950 to 6695 bp of the H19 upstream region revealed marked variations in the methylation patterns in fetal, adult, and neoplastic liver. In the fetal liver, equal proportions of hyper- and hypomethylated strands revealed the differentially methylated status of the parental alleles, but in neoplastic liver a pronounced change in the pattern of methylation was observed with a distinct change to hypomethylation in the short segments between 2984 and 3301 bp, 6033-6123 bp, and 6518-6548 bp. These results indicated that methylation of all cytosines in this region may contribute to the imprinting status of the rat H19 gene. This phenomenon of differential methylation-related epigenetic alteration in the key cis-regulatory domains of the H19 promoter influences switching to biallelic expression in hepatocellular carcinogenesis. Similar to mouse and human, we showed that the zinc-finger CCTCC binding factor (CTCF) binds to the unmethylated CTCF binding site in the upstream region to influence monoallelic imprinted expression in fetal liver. CTCF does not appear to be rate limiting in fetal, normal, and neoplastic liver. 3' to the CTCF binding sites, another DNA region exhibits methylation of CpG's in both DNA strands in adult liver, retention of the imprint in fetal liver, and complete demethylation in neoplastic liver. In this region is also a putative binding site for a basic helix-loop-helix leucine-zipper transcription factor, TFEB. The differential CpG methylation seen in the adult that involves the TFEB binding site may explain the lack of expression of the H19 gene in adult normal liver. Furthermore, these findings demonstrate that the loss of imprinting of the H19 gene in hepatic neoplasms of the SD Alb SV40 T Ag transgenic rat is directly correlated with and probably the result of differential methylation of CpG dinucleotides in two distinct regions of the gene that are within 4 kb 5' of the transcription start site. Cytogenetic analysis of hepatocytes in the transgenic animal prior to the appearance of nodules or neoplasms indicates a role of such loss of imprinting in the very early period of neoplastic development, possibly the transition from the stage of promotion to that of progression.
5' Untranslated Regions↗
Three-dimensional reconstruction from serial sections in PC-Windows platform by using 3D_Viewer.
Three-dimensional (3D) reconstruction from serial sections allows identification of objects of interest in 3D and clarifies the relationship among these objects. 3D_Viewer, developed in our laboratory for this purpose, has four major functions: image alignment, movie frame production, movie viewing, and shift-overlay image generation. Color images captured from serial sections were aligned; then the contours of objects of interest were highlighted in a semi-automatic manner. These 2D images were then automatically stacked at different viewing angles, and their composite images on a projected plane were recorded by an image transform-shift-overlay technique. These composition images are used in the object-rotation movie show. The design considerations of the program and the procedures used for 3D reconstruction from serial sections are described. This program, with a digital image-capture system, a semi-automatic contours highlight method, and an automatic image transform-shift-overlay technique, greatly speeds up the reconstruction process. Since images generated by 3D_Viewer are in a general graphic format, data sharing with others is easy. 3D_Viewer is written in MS Visual Basic 6, obtainable from our laboratory on request.
Automation↗
A potent modifier of liver cancer risk on distal mouse chromosome 1: linkage analysis and characterization of congenic lines.
The C3H/HeJ (C3H) and CBA/J (CBA) mouse strains are classical mouse models of cancer susceptibility, exhibiting high risks for both spontaneous and chemically induced liver cancer. By analysis of backcrosses and intercrosses between C3H or CBA and resistant B6 mice, we have mapped a potent modifier of hepatocellular carcinoma development to distal chromosome 1, linked to the marker D1Mit33 with combined LOD(W) scores of approximately 5.9 (C3H) and 6.5 (CBA). We previously identified this region as one of two that modify susceptibility in the more distantly related C57BR/cdJ (BR) strain. Congenic B6.C3H(D1Mit5-D1Mit17) and B6.BR(D1Mit5-D1Mit17) mice developed significantly more liver tumors than B6 mice did (6- to 13-fold, P < 10(-11), in males; 3- to 4-fold, P < 10(-3), in females). Thus, distal chromosome 1 carries one or more genes that are sufficient to confer susceptibility to liver cancer.
Animals↗
A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.
PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.
Adenocarcinoma↗
Crystal structure of serine dehydratase from rat liver.
SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine.
Animals↗
A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer.
PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.
Adenocarcinoma↗
Biallelic expression of the H19 gene during spontaneous hepatocarcinogenesis in the albumin SV40 T antigen transgenic rat.
Previous studies in this laboratory have demonstrated that the earliest cytogenetic alteration in the development of hepatic neoplasms in a transgenic strain of rats bearing the albumin Simian virus 40 T antigen (Alb SV40 T Ag) construct was a duplication of the chromosome 1q4.1-1q4.2 band. In this region, in the rat genome a cluster of linked imprinted genes occurs. One of these imprinted genes, H19, which is expressed in fetal liver but not in adult liver, was found to be expressed in virtually all neoplasms investigated. A single-nucleotide polymorphic marker in the H19 coding sequence was identified in two rat strains and utilized for the investigation of H19 imprinting. Our results reveal monoallelic expression of the maternal gene in fetal liver, but biallelic expression of the H19 gene in liver neoplasms, thus demonstrating the basis for the deregulation of the imprinted gene expression during hepatocarcinogenesis. These results suggest that the loss of genomic imprinting of the H19 gene found in the liver neoplasms of the Alb SV40 T Ag rat may result not from allelic loss, but from adverse changes in the epigenetic imprints present in the 5'-upstream region of the H19 promoter of the parental alleles.
Albumins↗
An improved stereologic method for three-dimensional estimation of particle size distribution from observations in two dimensions and its application.
Single enzyme-altered hepatocytes; altered hepatic foci (AHF); and nodular lesions have been implicated, respectively in the processes of initiation, promotion, and progression in rodent hepatocarcinogenesis. Qualitative and quantitative analyses of such lesions have been utilized both to identify and to determine the potency of initiating, promoting, and progressor agents in rodent liver. Of a number of possible parameters determined in the study of such lesions, estimation of the number of foci or nodules in the liver is very important. The method of Saltykov has been used for estimating the number of AHF in rat liver. However, in practice, the Saltykov calculation has at least two weak points: (a) the size class range is limited to 12, which in many instances is too narrow to cover the range of AHF data obtained; and (b) under some conditions, the Saltykov equation generates negative values in several size classes, an obvious impossibility in the real world. In order to overcome these limitations in the Saltykov calculations, a study of the particle size distribution in a wide-range, polydispersed sphere system was performed. A stereologic method, termed the 25F Association method, was developed from this study. This method offers 25 association factors that are derived from the frequency of different-sized transections obtained from transecting a spherical particle, thus expanding the size class range to be analyzed up to 25, which is sufficiently wide to encompass all rat AHF found in most cases. This method exhibits greater flexibility, which allows adjustments to be made within the calculation process when NA((k,k)), the net number of transections from the same size spheres, was found to be a negative value, which is not possible in real situations. The reliability of the 25F Association method was tested thoroughly by computer simulation in both monodispersed and polydispersed sphere systems. The test results were compared with the original Saltykov method. We found that the 25F Association method yielded a better estimate of the total number of spheres in the three-dimensional tissue sample as well as the detailed size distribution information. Although the 25F Association method was derived from the study of a polydispersed sphere system, it can be used for continuous size distribution sphere systems. Application of this method to the estimation of parameters of preneoplastic foci in rodent liver is presented as an example of its utility. An application software program, 3D_estimation.exe, which uses the 25F Association method to estimate the number of AHF in rodent liver, has been developed and is now available at the website of this laboratory.
Animals↗
Localization and hormonal control of serine dehydratase during metabolic acidosis differ markedly from those of phosphoenolpyruvate carboxykinase in rat kidney.
Serine dehydratase (SDH) is abundant in the rat liver but scarce in the kidney. When administrated with dexamethasone, the renal SDH activity was augmented 20-fold, whereas the hepatic SDH activity was affected little. In situ hybridization and immunohistochemistry revealed that SDH was localized to the proximal straight tubule of the nephron. To address the role of this hormone, rats were made acidotic by gavage of NH(4)Cl. Twenty-two hours later, the SDH activity was increased three-fold along with a six-fold increment in the phosphoenolpyruvate carboxykinase (PEPCK) activity, a rate-limiting enzyme of gluconeogenesis. PEPCK, which is localized to the proximal tubules under the normal condition, spreads throughout the entire cortex to the outer medullary rays by acidosis, whereas SDH does not change regardless of treatment with dexamethasone or NH(4)Cl. When NH(4)Cl was given to adrenalectomized rats, in contrast to the SDH activity no longer increasing, the PEPCK activity responded to acidosis to the same extent as in the intact rats. A simultaneous administration of dexamethasone and NH(4)Cl into the adrenalectomized rats fully restored the SDH activity, demonstrating that the rise in the SDH activity during acidosis is primarily controlled by glucocorticoids. The present findings clearly indicate that the localization of SDH and its hormonal regulation during acidosis are strikingly different from those of PEPCK.
Acidosis↗
Pathology of mouse models of intestinal cancer: consensus report and recommendations.
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Animals↗
A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer.
PURPOSE: The purpose of this study was to define the toxicity, pharmacokinetics, and clinical activity of the combination of ISIS 2503, an oligodeoxynucleotide antisense inhibitor of H-ras, and gemcitabine in patients with advanced solid tumors. EXPERIMENTAL DESIGN: The target dose of ISIS 2503 on this study was 6 mg/kg/day. Twenty-seven patients (16 male, 11 female) received 97 treatment courses (median, 2; range, 1-13). Nineteen patients were treated with a fixed gemcitabine dose of 1000 mg/m(2) on days 1 and 8 and two escalating doses of ISIS 2503 (4 and 6 mg/kg/day) as a 14-day continuous infusion starting on day 1. In addition, 8 patients (5 male, 3 female) received a flat dose of ISIS 2503 based on ideal body weight. Cycles were repeated every 3 weeks. Toxicities, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded as maximum grade/patient for all treatment cycles. Pharmacokinetic analyses were performed to evaluate any interaction between these two agents. RESULTS: The most common nondose-limiting toxicity was hematological, manifested as neutropenia (5 grade 2, 7 grade 3, and 1 grade 4) and thrombocytopenia (10 grade 1, 5 grade 2, 5 grade 3, and 1 grade 4). Nonhematological toxicities included anorexia (7 grade 1, 3 grade 2, and 1 grade 3), nausea (10 grade 1 and 1 grade 3), fatigue (6 grade 1, 5 grade 2, and 3 grade 3), fever (6 grade 1, 2 grade 2, 1 and grade 3), and thrombosis associated with central lines (5). The plasma concentration of gemcitabine at the end of infusion was altered in the presence of ISIS 2503, leading to alterations on other pharmacokinetic parameters, but the observed differences were not clinically relevant. The plasma disposition of ISIS 2503 was not altered by gemcitabine coadministration. One partial response was documented in a heavily pretreated patient with metastatic breast cancer. Disease stabilization for greater than six cycles of treatment was observed in 5 patients. CONCLUSIONS: The combination of gemcitabine and ISIS 2503 was well tolerated and clinically active in this group of heavily pretreated patients. The recommended Phase II dose of gemcitabine (1000 mg/m(2)) and ISIS 2503 (6 mg/kg/day) warrants additional evaluation.
Adult↗
A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer.
PURPOSE: This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty patients with solid tumors received a median of 2.5 cycles (range 1-30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777. RESULTS: Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients. CONCLUSION: The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.
Adult↗
Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.
PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.
Administration, Oral↗
A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer.
BACKGROUND: Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA). PATIENTS AND METHODS: Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated. RESULTS: The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients. CONCLUSION: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.
Acridines↗
Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide.
OBJECTIVE: The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN-38 and SN-38 glucuronide (SN-38G). METHODS: Plasma concentrations were obtained during and up to 48 hours after a 90-minute continuous intravenous infusion of irinotecan (100-340 mg/m(2)) in 78 patients. Data splitting was used to create model-building and model-validation data sets. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolites that are dependent on the disposition of the parent compound. Relationships between patient attributes and estimates of clearance (CL) and volume of the central compartment for irinotecan, as well as CL and volume of the central compartment adjusted for the fraction metabolized for SN-38 and SN-38G, were explored by use of generalized additive models and graphic analysis. Selected covariates were introduced into the final population model by stepwise additions or deletions with the likelihood ratio test. RESULTS: SN-38 and SN-38G were shown to be formation rate-limited and were characterized by first-order rate constants of formation and elimination. Two subpopulations of SN-38 disposition were identified, presumably because of differences in the fraction of metabolite formed from the parent compound. Estimated irinotecan CL (25.2 L/h) was similar to that determined in other studies. Age and performance status were found to be important predictors of irinotecan CL, whereas variability in systemic exposure to the active metabolite, SN-38, was predicted by sex and hepatic function. CONCLUSION: The validated population pharmacokinetic model describing the disposition of irinotecan and 2 of its metabolites should facilitate the design of future studies to elucidate the relative contributions of the parent compound and SN-38 to the pharmacologic and toxic effects of irinotecan therapy.
Adult↗