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2.
Bone Marrow Transplant ; 27(3): 261-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11277173

ABSTRACT

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.


Subject(s)
Bone Marrow Transplantation/methods , Thrombopoietin/administration & dosage , Adult , Area Under Curve , Bone Marrow Transplantation/adverse effects , Breast Neoplasms/therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Graft Survival/drug effects , Humans , Injections, Intravenous , Middle Aged , Platelet Count , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/standards , Thrombocytopenia/drug therapy , Thrombocytopenia/etiology , Thrombopoietin/pharmacokinetics , Thrombopoietin/standards , Transplantation, Autologous/adverse effects , Transplantation, Autologous/methods
3.
Vet Rec ; 147(14): 400, 2000 Sep 30.
Article in English | MEDLINE | ID: mdl-11073006
5.
Stem Cells ; 16 Suppl 2: 199-206, 1998.
Article in English | MEDLINE | ID: mdl-11012192

ABSTRACT

Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia. This can be associated with significant bleeding; currently, it is treated with supportive platelet transfusions. Frequent platelet transfusions can cause alloimmunization which requires HLA-matched donors and more frequent blood transfusions, and transmission of both viral and bacterial infections via platelet transfusions remains a concern. Furthermore, thrombocytopenia can mandate a decrease in the dose intensity of cytotoxic therapy by causing either delays or dose reductions in therapy administration. An intervention that reduces the risk or shortens the duration of severe thrombocytopenia would represent an important medical advance. Thrombopoietin (TPO), a naturally occurring, glycosylated polypeptide that was cloned by Genentech in 1994, is capable of inducing differentiation of stem cells into megakaryocytes and accelerating the maturation of megakaryocytes, thereby increasing the platelet count. Recombinant human TPO (rHuTPO) is currently undergoing testing in phase 1 and 2 studies in patients receiving myelosuppressive or myeloablative therapy. For the purposes of illustration, preliminary safety and activity data from one ongoing phase 1 myelosuppression trial (rHuTPO in women with advanced gynecologic malignancies receiving carboplatin) and one ongoing phase 1 myeloablation trial (rHuTPO for peripheral blood progenitor cell mobilization prior to myeloablative chemotherapy for high risk breast cancer) will be presented.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Radiotherapy/adverse effects , Recombinant Proteins/administration & dosage , Thrombocytopenia/drug therapy , Thrombopoietin/administration & dosage , Adolescent , Adult , Aged , Blood Platelets/cytology , Blood Platelets/drug effects , Blood Platelets/metabolism , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Drug Therapy, Combination , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Humans , Middle Aged , Recombinant Proteins/adverse effects , Thrombopoietin/adverse effects
6.
J Clin Oncol ; 15(4): 1432-8, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9193336

ABSTRACT

PURPOSE: To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). PATIENTS AND METHODS: Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. RESULTS: There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. CONCLUSION: HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/pathology , Liver Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Hepatic Artery , Humans , Infusions, Intra-Arterial , Interferon alpha-2 , Interferon-alpha/administration & dosage , Leucovorin/administration & dosage , Liver Neoplasms/secondary , Male , Middle Aged , Recombinant Proteins , Survival Analysis , Treatment Failure , Treatment Outcome
7.
Gastroenterology ; 112(3): 776-82, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9041239

ABSTRACT

BACKGROUND & AIMS: The nonspecific cross-reacting antigen (NCA) is a cell adhesion molecule, and the messenger RNA for NCA is overexpressed in 92% of colorectal carcinomas. The aim of this study was to determine the cis-acting elements that may be responsible for the expression of NCA. METHODS: Deletion mutants of the 5' flanking sequence and first intron were ligated into chloramphenicol acetyltransferase expression vectors, transfected into Chinese hamster ovary (CHO), DiFi, and HT-29 human colorectal carcinoma cells, and BxPC-3 and MDAPanc-28 human pancreatic carcinoma cells. The amount of acetylated chloramphenicol was determined to show the presence and activity of cis-acting sequences. RESULTS: The 5' flanking sequence functions as a promoter in all of cell lines and contains negative regulatory and enhancer sequences. The minimal promoter is active in Chinese hamster ovary and HT-29, though not in MDAPanc-28 cells. The first intron contains a silencer capable of suppressing a heterologous promoter. CONCLUSIONS: The results show cis-acting sequences within and 5' to the NCA gene, which appear to play a role in the expression of this gene in malignant tissues. Some of these sequences function in a cell type-specific manner. Further studies of these elements may provide insight into the mechanisms of the abnormal growth patterns of malignant cells.


Subject(s)
Antigens, Neoplasm/genetics , Cell Adhesion Molecules , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Membrane Glycoproteins/genetics , Animals , Base Sequence , CHO Cells , Cricetinae , HT29 Cells , Humans , Introns , Molecular Sequence Data , Promoter Regions, Genetic , Tumor Cells, Cultured
8.
J Clin Oncol ; 14(8): 2306-10, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8708721

ABSTRACT

PURPOSE: To evaluate the efficacy of paclitaxel administered to patients with unresectable adenocarcinomas of the gallbladder and biliary tree over 3 hours every 21 days. PATIENTS AND METHODS: Fifteen patients with unresectable and/or metastatic carcinoma of the gallbladder and bile ducts received intravenous paclitaxel over 3 hours after premedication with dexamethasone, diphenhydramine, and cimetidine. Treatment was repeated every 21 days, and one complete course of therapy was comprised of two such 21-day treatment cycles. The initial dose of paclitaxel was 170 mg/m2, and this was elevated to 200 mg/m2 due to tolerance within the initial patient cohort. RESULTS: All patients were assessable for both toxicity and response: 11 with bile duct cancer and four with gall-bladder carcinoma. Forty-three cycles of therapy were delivered during the trial (median, two), and one patient remains on treatment. No complete or partial responses were noted, although two patients achieved minor responses that lasted 2 and 2+ months, respectively. There were no deaths on this study, and all but one of the patients is still alive. The therapy was well tolerated, and hematologic and mucosal toxic effects were moderate and readily reversible, although significant neuromuscular adverse effects were noted. CONCLUSION: These findings indicate that paclitaxel, administered on this schedule, is tolerable, but is unlikely to have activity in metastatic carcinomas of the biliary tree. It is unclear whether a different regimen of paclitaxel, or another taxane, may have activity in these neoplasms.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Biliary Tract Neoplasms/drug therapy , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Bile Duct Neoplasms/drug therapy , Drug Administration Schedule , Female , Gallbladder Neoplasms/drug therapy , Humans , Male , Middle Aged , Neuromuscular Diseases/chemically induced , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Remission Induction
9.
J Clin Oncol ; 14(8): 2311-5, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8708722

ABSTRACT

PURPOSE: To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS: Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS: Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION: Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Neoplasms/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/therapy , Biliary Tract Neoplasms/drug therapy , Biliary Tract Neoplasms/mortality , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/mortality , Cholangiocarcinoma/therapy , Combined Modality Therapy , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Gallbladder Neoplasms/drug therapy , Gallbladder Neoplasms/mortality , Gallbladder Neoplasms/therapy , Humans , Infusions, Intravenous , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Male , Middle Aged , Recombinant Proteins , Remission Induction , Survival Rate
10.
Toxicol Pathol ; 24(4): 477-83, 1996.
Article in English | MEDLINE | ID: mdl-8864189

ABSTRACT

ZD0490 is an immunotoxin consisting of a mouse monoclonal antibody conjugated to recombinant ricin A-chain (rRAC). It was developed at Zeneca Pharmaceuticals as a treatment for certain antigen-bearing tumors. During safety evaluation studies in rats, a number of reversible inflammatory changes were seen. The synovial membranes of articular joints showed a marked degeneration and necrosis with an associated inflammation. When of mild severity only the synovial membrane was involved, but when more severe many adjacent tissues including the surface of the articular cartilage were affected. Some nonspecific skeletal muscle toxicity occurred. However, tongues from the intravenously (tail) dosed rats consistently showed inflammation specifically located in the ventral subepithelial area with myocyte degeneration and necrosis. Also, hepatic peliosis primarily located in the subcapsular areas was induced. Studies with rRAC alone indicated that ricin A-chain (RAC) is the component responsible for these findings. It is suggested that cells of a macrophage type with the ability to specifically bind RAC may at least in part determine the location and nature of the changes seen.


Subject(s)
Antineoplastic Agents/toxicity , Chemical and Drug Induced Liver Injury/pathology , Immunotoxins/toxicity , Ricin/toxicity , Synovial Membrane/pathology , Tongue/pathology , Animals , Antibodies , Antibodies, Monoclonal/toxicity , Female , Liver/pathology , Male , Rats , Rats, Wistar , Recombinant Proteins/toxicity
11.
Hum Exp Toxicol ; 15(1): 64-66, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8845213

ABSTRACT

Male and female C57BL/10J mice were fed 0 or 800 ppm cyproterone acetate (CPA) in the diet for 13 weeks. 1. Body weight was reduced (P > 0.001 at 13 weeks) by approximately 33%. 2. Seminal vesicle weights were reduced (P > 0.001) and showed histological atrophy, changes consistent with the anti-androgenic activity of the compound. 3. Liver weights were increased (P > 0.001) by +90% of control mean weights; hepatocyte hypertrophy and increased fat and glycogen were seen by light microscopy, and hyperplasia of smooth endoplasmic reticulin by transmission electron microscopy. 4. Assessment of liver mixed function oxidase activity demonstrated induction of cytochrome P450 enzymes, and increased isozyme 2B1/2 in males and 3A1 in both sexes was confirmed by immunohistochemical staining of liver sections. 5. An increase in bromodeoxyuridine (BrdU) labelling index of the liver was seen in females only. 6. This study is the first in a programme of work with CPA designed to investigate the effects of the compound in mice. It demonstrates that the hepatic effects of the compound which have been described in the rat also occur in mice.


Subject(s)
Androgen Antagonists/toxicity , Cyproterone Acetate/toxicity , Androgen Antagonists/pharmacokinetics , Animals , Antimetabolites/toxicity , Body Weight/drug effects , Bromodeoxyuridine/toxicity , Cyproterone Acetate/pharmacokinetics , Female , Immunohistochemistry , Liver/enzymology , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Microsomes, Liver/ultrastructure , Mixed Function Oxygenases/metabolism , Organ Size/drug effects , Rats
13.
Cancer ; 76(10): 1709-14, 1995 Nov 15.
Article in English | MEDLINE | ID: mdl-8625038

ABSTRACT

BACKGROUND: Metastatic colorectal cancer is generally incurable. The most active regimen available, 5-fluorouracil (5-FU) and folinic acid (Leucovorin), produces response rates of approximately 25% to 30%. Methyl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the addition of methyl-lomustine would have on response, duration of survival, and survival rates in patients with advanced colorectal cancer. METHODS: The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/m2), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m2), and Leucovorin (500 mg/m2). The FL treatment arm consisted of the administration of 5-FU and Leucovorin as described above. Patients were evaluated for response and toxicity after each 8-week cycle. RESULTS: Of 319 patients included in this trial, 297 (93.1%) had disease evaluable for response and toxicity: 145 received MFL, and 152 received FL. In this trial, 526 courses of MFL and 529 courses of FL were administered. Methyl-lomustine/5-FU/Leucovorin treatment resulted in 4 complete and 30 partial responses (response rate, 21.9%), and FL treatment resulted in 9 complete and 33 partial responses (response rate, 26.4%). There was no significant difference in median survival duration between patients in the two arms (MFL = 48 weeks, FL = 51 weeks). However, MFL was significantly more toxic with greater myelosuppression than was FL (Grade 3-4 neutropenia: MFL = 56 patients, FL = 27 patients, P < 0.001; Grade 3-4 thrombocytopenia: MFL = 49 patients, FL = 2 patients, P < 0.001; Grade 3-4 anemia: MFL = 15 patients, FL = 6 patients, P < 0.001; and more prolonged median duration of granulocytopenia: MFL = 9 days, FL = 7 days, P < 0.001; and thrombocytopenia: MFL = 14 days, FL = 7.5 days, P < 0.001). CONCLUSION: Because the addition of methyl-lomustine in the MFL schedule markedly increased the toxicity of the regimen and because the FL regimen was as effective as MFL, the authors recommend that Leucovorin and 5-FU remain the treatment choice for treating patients with metastatic colorectal cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/mortality , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Semustine/administration & dosage
14.
J Clin Oncol ; 12(11): 2296-300, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7964943

ABSTRACT

PURPOSE: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS: Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Leucovorin/therapeutic use , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Female , Humans , Leucovorin/adverse effects , Male , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Tegafur/administration & dosage , Tegafur/adverse effects , Uracil/administration & dosage , Uracil/adverse effects
15.
Shock ; 1(4): 273-8, 1994 Apr.
Article in English | MEDLINE | ID: mdl-7735961

ABSTRACT

Polymorphonuclear neutrophils (PMNs) have been implicated in microvascular injury following ischemia and reperfusion (I/R) but the relative contribution of obstruction versus toxic mediators is not well defined. Therefore, the present study was performed to determine the contribution of exogenous or endogenous activation on PMN-induced microvascular and hepatocyte injury. Rat livers were isolated and perfused at constant pressure with Krebs buffer with red cells (Hct-10%) and monitored for perfused sinusoids (PS) and dead hepatocytes (propidium iodide-stained, DH) by intravital microscopy. PMNs isolated from the peritoneum after oyster glycogen injection were added to the perfusate either without or with activation by phorbol myristate acetate (PMA, 160 nM). Unactivated PMNs stuck in the liver but had no significant effect on either perfused sinusoids (11.1 +/- .4/field, unactivated PMNs versus 11.9 +/- .5/field, the time-matched control) or dead hepatocytes (1.2 +/- .4/field, unactivated PMNs versus 1 +/- .3/field, the time-matched control). Infusion of PMA-activated PMNs resulted in significant decrease in perfused sinusoids and increase in DH (9.5 +/- .3/field for PS and 3.2 +/- .6/field for DH, respectively). In contrast, when PMNs were "activated" by infusion into a liver previously made ischemic for 30 min, DH were significantly increased after 60 min (26.2 +/- 4.5/field, I/R plus PMNs versus 12.4 +/- 2/field, I/R only) but perfused sinusoids were not different from ischemia alone. These results demonstrate that oxidatively quiescent PMNs do not cause cellular or microvascular injury in spite of microvascular accumulation. Activated PMNs damage microcirculation or hepatocytes depending on the nature of the activation.


Subject(s)
Liver/blood supply , Liver/injuries , Neutrophils/physiology , Reperfusion Injury/etiology , Animals , Cell Death , Disease Models, Animal , In Vitro Techniques , Liver/pathology , Male , Microcirculation/injuries , Neutrophils/drug effects , Rats , Rats, Sprague-Dawley , Reperfusion Injury/pathology , Tetradecanoylphorbol Acetate/pharmacology
16.
Cancer ; 72(9): 2560-3, 1993 Nov 01.
Article in English | MEDLINE | ID: mdl-8402476

ABSTRACT

BACKGROUND: Mitoxantrone is an anthraquinone derivative that has demonstrated encouraging preclinical and clinical activity against a variety of human carcinoma cell lines and malignancies. Three Phase II studies of systemically administered mitoxantrone in patients with colorectal carcinoma failed to demonstrate any therapeutic activity, as did four Phase II studies of intravenous mitoxantrone in hepatocellular carcinoma. Two additional trials demonstrated limited activity when administered intravenously to patients with hepatocellular carcinoma. However, because this drug exhibits a steep dose-response curve, a Phase I-II trial of mitoxantrone by hepatic arterial infusion was initiated. METHODS: Patients with hepatocellular carcinoma and metastatic colorectal carcinoma with liver only or liver-predominant disease were eligible for therapy. All patients underwent the placement of a percutaneous hepatic arterial catheter before each course of therapy, and the first cohort of patients was treated at 10 mg/m2/course on day 1 on a 28-day cycle. Dosages were escalated in increments of 2 mg/m2/course based on side effects and tolerance. RESULTS: Twenty-eight patients with bidimensionally measurable unresectable, liver-predominant disease were entered into this trial. The therapy was well tolerated, with only 5 courses of 55 being complicated by neutropenia and none associated with fever. Only one patient required a dosage reduction on the basis of toxicity (neutropenia). No complete or partial responses were observed. CONCLUSION: These data are consistent with a lack of therapeutic activity of mitoxantrone when administered by hepatic arterial infusion for the treatment of hepatocellular carcinoma or metastatic colorectal cancer.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma/drug therapy , Liver Neoplasms/drug therapy , Mitoxantrone/administration & dosage , Adult , Aged , Carcinoma/secondary , Colorectal Neoplasms/pathology , Female , Hepatic Artery , Humans , Infusions, Intra-Arterial , Liver Neoplasms/secondary , Male , Middle Aged , Mitoxantrone/therapeutic use
17.
Cancer Invest ; 11(6): 667-9, 1993.
Article in English | MEDLINE | ID: mdl-8221199

ABSTRACT

Merbarone, a nonsedating derivative of thiobarbituric acid that has demonstrated antineoplastic activity against a variety of murine tumors, was evaluated in a phase II trial in patients with advanced, measurable adenocarcinoma of the pancreas. Seventeen patients were treated at a starting dose of 1000 mg/m2/day for 5 days by continuous intravenous infusion; the dose was escalated in accordance with the toxicity experienced, and no dosage reductions owing to toxicity were required. No complete or partial responses were observed, and only one minor response was documented, suggesting that merbarone is ineffective against pancreatic cancer at the doses and schedule in which it was administered in this trial.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Pancreatic Neoplasms/drug therapy , Thiobarbiturates/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Female , Humans , Male , Middle Aged , Nausea/chemically induced , Thiobarbiturates/adverse effects , Vomiting/chemically induced
19.
Invest New Drugs ; 10(3): 211-3, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1428730

ABSTRACT

Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measurable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m2 over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologic or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/administration & dosage , Colorectal Neoplasms/drug therapy , Depsipeptides , Peptides, Cyclic/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Peptides, Cyclic/adverse effects
20.
Gastroenterology ; 103(1): 98-102, 1992 Jul.
Article in English | MEDLINE | ID: mdl-1612363

ABSTRACT

The authors have previously reported that a messenger RNA (mRNA) bearing 60% homology to elongation factor 1 gamma in Artemia salina was overexpressed in 7 of 9 pancreatic tumors relative to normal appearing adjacent tissue. The purpose of the present study was to determine if this pattern of overexpression is also detected in colorectal carcinoma. Overexpression was observed in 25 of 29 colorectal carcinomas, relative to normal adjacent tissue. Of them, mRNA was overexpressed in 2 tumors classified as Dukes' D, in 8 of 11 tumors classified as Dukes' B2, and in 15 of 16 tumors classified as Dukes' C2.


Subject(s)
Adenocarcinoma/genetics , Colonic Neoplasms/genetics , Gene Expression , Peptide Elongation Factors/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Base Sequence , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Neoplasm Staging , Peptide Elongation Factor 1 , RNA, Neoplasm/metabolism
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