Search PubMed⌕ Search

Biomedical subjects

H C Pitot

Publications and source records attributed to H C Pitot.

At least 19 recordsLinked to original sources
PubMed2002

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.

Adenocarcinoma↗
PubMed2001

A Phase II study of high-dose paclitaxel in patients with advanced neuroendocrine tumors.

BACKGROUND: New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte-colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia. METHODS: Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m(2) every 3 weeks plus GCSF at a dose of 5 microg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/microL. RESULTS: All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0-0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6-6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0-1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2-5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients). CONCLUSIONS: Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended.

Adenoma, Islet Cell↗
PubMed2001

A clonal growth model: time-course simulations of liver foci growth following penta- or hexachlorobenzene treatment in a medium-term bioassay.

A combination of experimental and simulation approaches were used to analyze the clonal growth of preneoplastic, enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen. Male Fisher 344 rats, 8 weeks of age, were initiated with a single dose (200 mg/kg, i.p.) of diethylnitrosamine (DEN). Beginning 2 weeks later, animals were exposed to daily gavage consisting of 0.1 mmol/kg pentachlorobenzene (PECB) or hexachlorobenzene (HCB) in corn oil vehicle for 6 weeks. Partial hepatectomy was performed 3 weeks after initiation. Experimental data including liver weight, hepatocyte density (number of hepatocytes/unit volume), 5-bromo-2'-deoxyuridine-labeling index for analysis of cell division rate, and number and volume of glutathione-S-transferase pi-positive foci were collected 23, 26, 28, 47, or 56 days after initiation. Model parameters describing liver growth were obtained directly from the experimental data. The probability of mutation/division of normal cells and the growth rate of initiated cells were inferred by a comparison of model outcomes with the observed time courses of foci development. To describe the time-dependent increases in foci volume and the concomitant reduction of foci number observed in all treatment groups, the calibrated model for the DEN controls incorporated the hypothesis of two initiated cell populations (referred to as A and B cells) within the framework of the two-stage model. The B cells are initiated cells that have a selective growth advantage under conditions that inhibit the growth of A cells and normal hepatocytes. The parameter values defined in the DEN controls were used to evaluate experiments involving the administration of PECB or HCB. Both PECB and HCB caused a significant increase in foci volume compared with the DEN controls. HCB treatments resulted in increased proliferation of normal hepatocytes, which was not observed for PECB under the same treatment regimen. The best description of the data resulted from the model incorporating the hypothesis that PECB and HCB promoted the growth of foci via increased net growth rates of B cells. We present here a biologically based clonal growth simulation platform to describe the growth of preneoplastic foci under experimental manipulations of initiation-promotion studies. This simulation work is an example of quantitative approaches that could be useful for the analysis of other initiation-promotion studies.

Animals↗
PubMed2001

Limited sampling models for CPT-11, SN-38, and SN-38 glucuronide.

PURPOSE: We developed limited sampling models (LSMs) for predicting the area under the curve (AUC) of irinotecan (CPT-11) and its metabolites SN-38 and SN-38 glucuronide (SN-38G). PATIENTS AND METHODS: Regression models were developed based on data from a phase I clinical trial involving 34 patients with advanced solid tumor malignancies who received CPT-11 as a 90-min infusion on an every 3-week dosing schedule. Multiple stepwise regression procedures were supplemented by all possible subsets regression analysis. Alternative clinically based and empirically derived LSMs were determined via model validation assessment including bootstrap simulation testing. RESULTS: The best LSMs for CPT-11 AUC included concentrations recorded at the end of infusion and 4 h later with an option to include a blood draw at 7.5 h from infusion start. For SN-38 and SN-38G AUC, optimal LSMs included the additional metabolite concentration at 48 h after infusion. The LSMs were able to predict most patient AUC values to within 10% of the true value. CONCLUSION: CPT-11 AUC can be modeled with acceptable accuracy using only two or three plasma concentration time-points. A variety of LSM alternatives provided comparable accuracy in predicting AUC. Given the wide variety of LSM alternatives, clinical considerations and patient burden become more important performance parameters than statistical considerations for the choice of time-points in constructing LSMs.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Phase I trial of gemcitabine and CPT-11 given weekly for four weeks every six weeks.

BACKGROUND: Our previous studies have shown that the in vitro cytotoxicity of gemcitabine and SN-38, the active metabolite of irinotecan (CPT-11), is synergistic in human tumor cell lines. PATIENTS AND METHODS: Twenty-four patients with solid tumors, refractory to standard chemotherapy or for whom no effective therapy existed (age range 31-74; 7 female, 17 male; ECOG PS 0 = 12, 1 = 11, 2 = 1), received gemcitabine and CPT-11 weekly for four weeks out of every six weeks. Fifty courses of treatment (median 2, range 1-8) were given through five dose levels of gemcitabine/CPT-11 (600/75, 800/75, 800/100, 1000/100, 1000/125 mg/m2). RESULTS: Grade 3 and 4 neutropenia occurred in eight and two patients, respectively. Grade 3 and 4 thrombocytopenia occurred in one and three patients, respectively. Hematologic toxicity resulted in > or = 2 missed doses of treatment in two out of six patients and was therefore dose limiting at gemcitabine 1000 mg/m2 and CPT-11 125 mg/m2. Grade 3 and 4 diarrhea occurred in two and one patients, respectively. Other moderate non-hematologic toxicities included alopecia, anorexia, fatigue, nausea, vomiting, and weight loss. CONCLUSIONS: The maximum tolerated dose for this study recommended for phase II testing is gemcitabine 1000 mg/m2 and CPT-11 100 mg/m2. A partial response was seen in transitional cell carcinoma.

Adult↗
PubMed2001

Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity. PATIENTS AND METHODS: BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks. RESULTS: Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration. CONCLUSIONS: The recommended dose for further testing is 800 mg p.o. b.i.d.

Adult↗
PubMed2001

Immunohistochemical localization and semi-quantitation of hepatic tamoxifen-DNA adducts in rats exposed orally to tamoxifen.

Administration of tamoxifen (TAM) has been shown to induce hepatocellular carcinogenesis and TAM-DNA adduct formation in rat liver. Here we present TAM-DNA adduct localization and semi-quantitation in hepatic tissue of rats by immunohistochemical staining followed by image analysis. We have also used a quantitative immunoassay to provide a validation for the immunohistochemical values. Rats were fed diets containing 0, 5, 50, 150 or 500 p.p.m. TAM for 45 weeks. Serial sections of paraffin-embedded liver were stained for TAM-DNA adducts using a polyclonal TAM-DNA antiserum. Subsequently, visualization of TAM-DNA adducts was performed by peroxidase-conjugated secondary antibody-mediated signal amplification using biotinyl tyramide followed by streptavidin-alkaline phosphatase and fast red. Semi-quantitation of nuclear color intensity was achieved with an Automated Cellular Imaging System (ACIS), with a detection limit of 1 TAM-DNA adduct per 10(7) nt for these experiments. In parenchymal cells of liver sections from TAM-exposed animals a dose-dependent increase in nuclear staining was observed by ACIS and the TAM-DNA adduct levels determined by ACIS were validated in liver DNA by quantitative chemiluminescence immunoassay (CIA). Comparison of semi-quantitative values determined by ACIS with quantitative values determined by CIA showed a strong correlation (r = 0.924) between the two methods. At 45 weeks of TAM exposure the liver cytoplasm contained placental glutathione S-transferase (GST-p)-positive foci, as indicated by new fuchsin staining. Staining of serial sections revealed a relative lack of TAM-DNA adducts within these enzyme-altered foci. In addition, some GST-p foci contained islands of cells that did not stain for GST-p but were positive for TAM-DNA adduct formation. This study validates the use of ACIS for TAM-DNA adduct formation and demonstrates that steady-state TAM-DNA adduct levels observed in livers of rats chronically fed TAM for several months increase in relation to dose. In addition, unlike the normal surrounding liver, preneoplastic GST-p-positive foci have virtually no TAM-DNA adducts.

Administration, Oral↗
PubMed2001

Aging lowers steady-state antioxidant enzyme and stress protein expression in primary hepatocytes.

It has been reported that the isolation and culture of primary hepatocytes can compromise cellular ability to constituitively express antioxidant enzyme (AE) genes, making it difficult to study their regulation ex vivo. In the present study, the steady-state expression of manganese-containing superoxide dismutase, copper- and zinc-containing superoxide dismutase, catalase, and glutathione peroxidase was assessed in primary hepatocytes isolated from young and senescent rats and cultured in MATRIGEL: There was no change in steady-state superoxide dismutase protein or activity levels in cells collected from young animals and cultured for 7 days. Catalase expression was initially increased, and then it declined 30%. In contrast, superoxide dismutase expression declined 60% and catalase expression declined 50% in cells from senescent animals. Constitutive and inducible 70-kDa heat shock protein expression increased coincident with declining AE levels in the young cells but not senescent cells. For both age groups, electron micrographs showed rounded hepatocytes with abundant rough endoplasmic reticulum, mitochondria, and peroxisomes. Hepatocytes were organized into clusters of 6-12 cells surrounding a large central lumen devoid of microvilli. Each cluster also contained smaller microvilli-lined lumens between adjacent hepatocytes that resembled canniculi. The plasma membranes of these lumens were sealed from the extracellular space by junctional complexes. Gap junctions in the plasma membrane suggest that hepatocytes were capable of intercellular communication. We conclude that the Matrigel system can be used to study AE regulation in primary hepatocytes from young and senescent animals, provided that experiments can be conducted within a time frame of 5-7 days in culture. These data also support the hypothesis that aging compromises hepatocellular ability to maintain AE status and upregulate stress protein expression.

Aging↗
PubMed2001

Future directions in adjuvant therapy for stage III colon carcinoma.

The current recommendation for adjuvant chemotherapy for patients with newly diagnosed stage III colon cancer involves 6 months of fluorouracil (5-FU) plus low- or high-dose leucovorin. In clinical trials performed throughout the world, several drugs have demonstrated either improved toxicity profiles or antitumor activity for patients with advanced colorectal carcinoma. Uracil and tegafur (UFT) and capecitabine (Xeloda) are two examples of new oral chemotherapy compounds with acceptable side-effect profiles in early adjuvant or advanced disease trials. Irinotecan (CPT-11, Camptosar) and oxaliplatin, when administered intravenously in combination with a 5-FU regimen, have both demonstrated significant antitumor effects for patients with advanced-stage disease. Other immunotherapies, including monoclonal antibodies and cancer vaccines, are being evaluated to help stimulate immune responses in patients with resected colon cancer. These agents are just a few examples of the new compounds being tested in the next generation of clinical trials for resected stage III colon cancer. Future and ongoing investigations will look to integrate these new therapies as we attempt to move beyond the era of 5-FU and leucovorin.

Antineoplastic Agents↗
PubMed2001

Animal models of neoplastic development.

The basic animal model for neoplastic development used by regulatory agencies is the two-year chronic bioassay developed more than 30 years ago and based on the presumed mechanism of action of a few potential chemical carcinogens. Since that time, a variety of other model carcinogenic systems have been developed, usually involving shorter duration, single organ endpoints, multistage models, and those in genetically-engineered mice. The chronic bioassay is still the "gold standard" of regulatory agencies despite a number of deficiencies, while in this country the use of shorter term assays based on single organ endpoints has not been popular. The multistage model of carcinogenesis in mouse epidermis actually preceded the development of the chronic two-year bioassay, but it was not until multistage models in other organ systems were developed that the usefulness of such systems became apparent. Recently, several genetically-engineered mouse lines involving mutations in proto-oncogenes and tumour suppressor genes have been proposed as additional model systems for use in regulatory decisions. It is likely that a combination of several of these model systems may be most useful in both practical and basic applications of cancer prevention and therapy.

Animals↗
PubMed2000

A North Central Cancer Treatment Group Phase II trial of 9-aminocamptothecin in previously untreated patients with measurable metastatic colorectal carcinoma.

BACKGROUND: Topoisomerase I inhibitors have demonstrated clinical activity in patients with metastatic colorectal carcinoma. The authors performed a Phase II study to evaluate the objective tumor response rate of 2 different doses and schedules of 9-aminocamptothecin (9-AC) in previously untreated patients with measurable recurrent metastatic colorectal carcinoma. METHODS: Fifty-one patients were registered. One schedule evaluated 9-AC given at 1100 microgram/m(2)/24 hours by continuous infusion for 72 hours along with granulocyte-colony stimulating factor at 5 microgram/kg/day on Days 5 through 12. Another schedule involved 9-AC at 480 microgram/m(2)/24 hours by continuous infusion for 120 hours on Days 1, 8, and 15 given every 4 weeks. RESULTS: Forty-eight of 51 patients (94%) were evaluable (28 patients who received 72-hour infusion and 20 patients who received 120-hour infusion) for response and toxicity. Significant hematologic toxicities were encountered, especially with the 72-hour infusion schedule, in which 43% (12 of 28) and 28% (8 of 28) experienced Grade 4 (National Cancer Institute Common Toxicity Criteria) leukopenia and thrombocytopenia, respectively. Grade 4 neutropenia was encountered in 61% (17 of 28) and 11% (2 of 19) of patients on the 72-hour and 120-hour infusion schedules, respectively. Diarrhea, nausea, vomiting, and hepatotoxicity were troublesome nonhematologic toxicities. Seventy-nine percent (11 of 14) and 57% (4 of 7) of the patients experiencing Grade 3 or 4 nonhematologic toxicity were on the 72-hour infusion schedule. Three patients died of chemotherapy-related toxicity. One response was observed in 48 evaluable patients (2%). CONCLUSIONS: 9-AC did not demonstrate sufficient antitumor activity and had unacceptable toxicity in previously untreated patients with metastatic colorectal carcinoma.

Adult↗
PubMed2000

Characterization of the major DNA adducts in the liver of rats chronically exposed to tamoxifen for 18 months.

Our previous study has shown that chronic exposure to tamoxifen (TAM) induced formation of high levels of DNA adducts in the liver, the target tissue of TAM-induced carcinogenesis in rats. One of the major DNA adducts (spot 1), as detected by 32P-postlabeling, accounted for 53% of the total adducts. To characterize this major adduct, the current study has compared spot 1 with two previously identified TAM-DNA adducts, i.e. alpha-TAM-N2-deoxyguanine (alpha-TAM-N2-dG) and alpha-N-desmethyl TAM-N2-deoxyguanine (alpha-N-dmTAM-N2-dG) by various rechromatography methods. It was found that spot 1 was further resolved into two fractions during rechromatography analysis, one fraction co-migrated with the alpha-TAM-N2-dG and the other fraction co-migrated with the alpha-N-dmTAM-N2-dG. These findings have demonstrated that chronic exposure to tamoxifen induced the same major DNA adducts, i.e. alpha-TAM-N2-dG and alpha-N-dmTAM-N2-dG as those detected in acutely exposed rats.

Animals↗
PubMed2000

Genome-wide loss of heterozygosity analysis of chemically induced rat hepatocellular carcinomas reveals elevated frequency of allelic imbalances on chromosomes 1, 6, 8, 11, 15, 17, and 20.

Neoplastic development is a multistep process that involves the stochastic accumulation of heritable genetic alterations in proto-oncogenes, DNA repair genes, and tumor suppressor genes. Loss of heterozygosity (LOH) analysis has been used successfully to identify the genetic determinants of neoplastic development, including tumor suppressor genes, in several species and organs but not in the rat liver. We report the results of a sensitive genome-wide LOH analysis of rat hepatocellular carcinomas (HCCs). Heterozygous rats (Wistar-Furth x Fisher 344) were subjected to an Initiation-Promotion-Progression (IPP) protocol of hepatocarcinogenesis. Two weeks after initiation (by partial hepatectomy, 10 mg/kg diethylnitrosamine), the rats were placed on a diet containing 0.05% phenobarbital (PB). After 24 wk of PB promotion, the rats received either 100 or 1 50 mg/kg ethylnitrosourea. Hepatocellular tumors were resected after a total of 76wk of PB promotion. LOH analysis was completed on 26 HCCs by using 60 microsatellite markers covering all 20 rat autosomes and chromosome X. While 85% of the HCCs had one or more allelic imbalances, the average HCC had 3.3 allelic imbalances (range 0-9). A conditional hypothesis-testing method called the Hot-Cold model was used to determine the location of statistically significant elevations in the frequency of allelic imbalances. Elevated allelic imbalances were observed on chromosomes 1q, 6, 8, 11, 15, 17, and 20p. Together, these allelic imbalances suggest that the retinoblastoma and insulin-like growth factor genes as well as the resistance to chemical carcinogenesis (rcc) locus may be involved in HCC development in the rat but that LOH of the p53 gene is not. The elevated rate of allelic imbalances on chromosomes 8,11, and 17 may indicate the location of undiscovered tumor suppressor genes important to neoplastic development in rat liver. Microdissection-based LOH analysis of HCC revealed that contamination of non-neoplastic and nonhepatocellular tissue was not masking LOH in the whole-tumor analysis. There were no statistically significant differences in the frequency of allelic imbalances between HCC of any differentiation state (histological grade). To the degree that it does not reflect differences in etiological factors, the absence of allelic imbalances in chromosomal regions containing the p53 and mamose-6-phosphate/insulin-like growth factor II receptor tumor suppressor genes and the generally low frequency of allelic imbalances in these tumors, suggests that LOH and allelic imbalances play a less significant role in the molecular pathogenesis of HCC in rats than humans.

Alleles↗
PubMed2000

Nuclear-labeling index analysis (NLIA), a software package used to perform accurate automation of cell nuclear-labeling index analysis on immunohistochemically stained rat liver samples.

The nuclear labeling index (labeled nuclei/100 nuclei) and the apoptotic index (apoptotic cells/100 cells) are important parameters of cell growth and death. Automatic counting of labeled nuclei is desirable since manual counting is tedious, time-consuming, and with a greater potential for inaccuracies. A nuclear-labeling index analysis (NLIA) software package was developed in this laboratory to perform the counting process automatically and accurately. This software package consists of an application program NLIA and a set of macros for obtaining nuclear data that is used in Scion Image. It is designed to work cooperatively with Scion Image, Adobe Photoshop, and Microsoft Office. NLIA has two basic functions: building nuclear data files and analyzing nuclear data. A color image captured from an immunohistochemically stained or autoradiographic sample is loaded into NLIA. Nuclear data can be entered into the program manually, automatically, or in combination. In the manual data entering mode, NLIA acts as an object-counting tool, while in the automatic mode it acts as a data picker: picking up the data generated by Scion Image into memory. A method to enter nuclear data (both labeled nuclei and unlabeled nuclei) in the automatic mode is described. The color image is processed in Adobe Photoshop, where the interested color ranges are selected and separated. These are then analyzed in Scion Image with the help of the macros for obtaining nuclear data. Since the advanced particle analysis function is used, the counting process is automatic and rapid. Data from thousands of nuclei can be obtained within seconds. To ensure the accuracy of the analysis, a nuclear data checking and edit feature is employed in NLIA: results of computer-generated counting can be compared with the original color image by overlaying the plot of counting results onto the original color image. In this way any computer counting mistakes can be easily discovered and corrected by the operator. Corrected nuclear data (including nuclear size, location, shape) are then stored in data files. These data files can be used in NLIA to obtain cell density and nuclear labeling indices. Because criteria for obtaining nuclear data (truncation diameter, shape factor) can be set by the operator in NLIA, nuclear size distribution and shape variation can be analyzed. This method provides a fast and accurate way to determine cell nuclear-labeling indices. Currently, Scion Image is a freeware on the internet, and NLIA software package is available from our lab home page. Methods presented here expand the Scion Image ability to analyze color images by using color separation techniques in a commercial graphic application. The instrumentation required can be relatively inexpensive, and the methods described may be useful in studies of cell kinetics, lesion growth, and tumor therapy.

Animals↗
PubMed2000

Review article: the stages of gastrointestinal carcinogenesis--application of rodent models to human disease.

The development of gastrointestinal cancer in humans and animals occurs through a consecutive series of stages termed initiation, promotion and progression. The characterization of each of these stages has been elucidated in several model systems as well as in human neoplasms. Both single, putatively initiated cells and preneoplastic foci have been identified by marker protein differences as well as by mutational changes. The promotion stage involves the clonal expansion of single initiated cells. Such expansion can be rapidly reversed by a variety of means, of which acute fasting (as exemplified in rat hepatocarcinogenesis) is among the most rapid and efficient. This reversal involves a selective apoptosis of preneoplastic cells and preneoplastic lesions, associated with a marked increase in expression of the proto-oncogene c-myc. Transition of cells from the stage of promotion to that of progression initially involves specific karyotypic alterations, as noted in both the rat liver model and human colon carcinogenesis. In the former, the transition appears to be associated with enhanced expression of the H119 imprinted putative tumour suppressor gene. Thus, the use of model systems may be applied directly to the human circumstance, increasing the potential both for rational prevention of gastrointestinal neoplasia and for new approaches to the therapy of neoplastic disease in the progression stage.

Animals↗
PubMed2000

Multiple polypeptide hormone expression in pancreatic islet cell carcinomas derived from phosphoenolpyruvatecarboxykinase-SV40 T antigen transgenic rats.

Transgenic rats carrying a PEPCK-SV40 large T-antigen (TAg) transgene rapidly develop numerous pancreatic islet cell neoplasms, the cells of which express TAg. Although many of the larger neoplasms contain relatively undifferentiated cells, many tumors contain areas of well-differentiated cells with abundant endoplasmic reticulum (ER) and secretory granules for endocrine hormones like those observed in normal pancreatic islets. In the well-differentiated lesions, glucagon-producing alpha-cells, insulin-producing beta-cells, and somatostatin-producing delta-cells are readily identifiable morphologically under the electron microscope. Beta-cells were observed in all normal and hyperplastic islets, and nests of these cells were scattered throughout the larger neoplasms. These nests varied from small clusters of epithelium-like cells that stain intensely for insulin, to sheets of small, basophilic cells that stain more diffusely for the hormone. Alpha-cells were also present in all of the normal and hyperplastic islets, but in larger hyperplastic islets, the peripheral localization was absent. Larger neoplasms contained many nests of glucagon-expressing cells, as well as scattered glucagon-producing single cells. Delta-cells were rarely observed in the hyperplastic islets and in the neoplasms. Blood-glucose levels were unaltered in the transgenic animals relative to their nontransgenic litter mates. Thus although these islet cell neoplasms express several polypeptide hormones, there is no obvious clinical effect of such expression in vivo.

Animals↗
PubMed2000

Phase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: preliminary evidence of clinical activity.

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).

Adult↗