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J G Beitz

Publications and source records attributed to J G Beitz.

12 recordsLinked to original sources
PubMed1999

Predictive value of preclinical toxicology studies for platinum anticancer drugs.

Rodent and nonrodent toxicology studies are currently expected to support Phase I trials of antineoplastic drugs in the United States. To determine the predictive value of these studies, we initiated a project to compare preclinical and clinical toxicity data within various drug classes. The first class analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from matching drug administration schedules were identified. The rodent LD10 (the dose that causes lethality in 10% of treated animals) or dog toxic dose high (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one-third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting toxicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies, respectively. Our data indicate that mice, rats, and dogs all had value in predicting a safe starting dose and the qualitative toxicities in humans for platinum anticancer compounds. The efficiency of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventionally permitted.

Animals↗
PubMed1995

Saporin toxins directed to basic fibroblast growth factor receptors effectively target human ovarian teratocarcinoma in an animal model.

BACKGROUND: The antitumor activity of the chemical conjugate and recombinant forms of the mitotoxin basic fibroblast growth factor (bFGF) saporin (SAP) and the bFGF receptor-directed immunotoxin 11A8-SAP against human ovarian teratocarcinoma PA-1 was examined in athymic nude mice. Alternative administration schedules to prolong therapeutic efficacy were explored. METHODS: Intravenous dosing (0.01-125 micrograms/kg) of chemical conjugate and recombinant bFGF-SAP or 11A8-SAP beginning 5 days after subcutaneous implantation of PA-1 cells was administered by i) weekly injection for 4 weeks, ii) continuous infusion for one week, or iii) daily injection five times a week for 4 weeks. RESULTS: Weekly injections (31.25 micrograms/kg) of chemical conjugate bFGF-SAP or 11A8-SAP, the latter of which is 25% the molarity of the former, resulted in mean tumor volumes that were, respectively, 35% or 52% of controls (day 30) and 52% or 76% of controls (day 60). Chemical conjugate or recombinant bFGF-SAP administered weekly resulted in mean tumor volumes that were, respectively, 51% or 77% (0.5 microgram/kg) and 42% or 31% (50 micrograms/kg) of controls (day 30). A mean tumor volume of 35% of controls (day 30) and of 49% of controls (day 60) were observed in animals treated by constant infusion of chemical conjugate bFGF-SAP (125 micrograms/kg, total dose). Alternatively, tumors of animals receiving daily injections (125 micrograms/kg, total dose) exhibited a mean volume of 21% of controls (day 30) and prolonged growth inhibition as demonstrated by a mean tumor volume of 22% of controls (day 60). CONCLUSIONS: These studies suggest a therapeutic potential for bFGF-receptor-directed saporin toxins in the treatment of ovarian teratocarcinoma and the importance of frequency of administration in achieving optimal tumor responses.

Animals↗
PubMed1995

Autocrine down-regulation of basic fibroblast growth factor receptors causes mitotoxin resistance in a human melanoma cell line.

The ability of melanoma to develop resistance to mitotoxins, growth-factor-directed anti-neoplastic agents that offer potential for the treatment of this highly refractory disease, may limit therapeutic efficacy. To address this problem, we developed a subcloned human melanoma cell line that is resistant to the mitotoxin composed of basic fibroblast growth factor conjugated to the ribosome-inactivating protein saporin. Resistance was caused by autocrine FGF ligands, which down-regulate bFGF receptors and reduce bFGF-saporin binding. Inhibiting the autocrine loop with suramin or with neutralizing antibodies to FGF up-regulated receptors and decreased resistance in vitro. Furthermore, suramin restored sensitivity in resistant tumor xenografts. These results suggest the potential of therapeutic modalities combining agents that neutralize growth factors with receptor-directed mitotoxins for targeting malignant melanoma either to prevent emergence of resistance or to circumvent resistance once it occurs.

Down-Regulation↗
PubMed1995

Phase I trial of high-dose infused zidovudine combined with leucovorin plus fluorouracil.

This phase I trial evaluated a high-dose, short-term infusion of zidovudine (AZT) following oral leucovorin (LV) and bolus 5-fluorouracil (FUra). Thirteen patients with metastatic cancer received 30 cycles of therapy. Plasma monitoring demonstrated a dose-dependent increase in peak plasma levels of AZT through the range of dose levels, from 104.3 +/- 8.7 microM at the 1.5 g/m2 dose of AZT to 1312.6 +/- 165.9 microM at the 11.0 g/m2 dose. While AZT did not potentiate the usual clinical toxicities of LV plus FUra, an unexpected finding of symptomatic hypotension during the AZT infusion was the dose-limiting toxicity in this trial. One partial response was observed in a previously untreated patient with metastatic colorectal cancer. The maximal tolerated dose of AZT, 7.0 g/m2 over 2 hr, is recommended for future phase II evaluation of this novel combination.

Adult↗
PubMed1993

Platelet-derived growth factor indirectly stimulates angiogenesis in vitro.

We evaluated the effect of platelet-derived growth factor (PDGF) on capillary formation using an in vitro angiogenesis model system in which microvascular fragments and myofibroblasts (Mfs) isolated from rat epididymal lipid tissues were grown in co-culture. In this system Mfs induce capillary formation by producing an endothelial cell growth factor and by secreting extracellular matrix components that cause endothelial cells to form cordlike structures. Addition of PDGF enhances in vitro capillary growth. Although some recently described microvascular endothelial cells display PDGF receptors and respond to PDGF, we found no evidence for direct PDGF action on the rat epididymal microvascular endothelial cells. Rather, we found that PDGF increased the proliferation of Mfs, as well as the production of Mf-derived endothelial cell growth factor and matrix collagen type I. Our results suggest that even in cases where the microvasculature lacks PDGF receptors, PDGF may accelerate capillary formation by activating connective tissue cells in the vicinity of endothelial cells.

Animals↗
PubMed1992

Antitumor activity of basic fibroblast growth factor-saporin mitotoxin in vitro and in vivo.

Many cancer cell lines express basic fibroblast growth factor (FGF) receptors, making them potential targets for the delivery of FGF-based cytotoxic compounds. To this end, we have investigated the antitumor activity of a novel mitotoxin, Fibroblast Growth Factor-saporin (FGF-SAP), a conjugate of FGF and the ribosome-inactivating protein, saporin. In vitro, FGF-SAP is cytotoxic for human melanoma, teratocarcinoma, and neuroblastoma cells expressing FGF-receptors. Mice treated with FGF-SAP i.v., on a variety of schedules, showed dramatic tumor growth inhibition with minimal toxicity. Thus, FGF-SAP appears to be a well-tolerated and potent antitumor agent. The potential of FGF-targeted cytotoxicity is discussed.

Animals↗
PubMed1992

Receptors for platelet-derived growth factor on microvascular endothelial cells.

Endothelial cells are widely thought to be unresponsive to platelet-derived growth factor (PDGF) and devoid of PDGF receptors. However, in examining the growth factor responses of microvascular endothelial cells isolated from human omental adipose tissue, we detected PDGF-induced tyrosine phosphorylation of an 180-kD glycoprotein, subsequently identified as the cellular receptor for PDGF by specific immunoprecipitation. Scatchard analysis of 125I-PDGF binding to human microvascular endothelial cells revealed 30,000 PDGF receptors/cell with a kD of 0.14 nM. PDGF stimulated tyrosine phosphorylation of PDGF and other cellular proteins in a dose- and time-dependent manner, with half-maximal receptor phosphorylation occurring at 0.3 nM recombinant human PDGF-BB within 1 min of PDGF exposure. Normal cellular consequences of receptor activation were also observed, including tyrosine phosphorylation of a 42-kD protein and serine phosphorylation of ribosomal protein S6. Furthermore, PDGF was mitogenic for these cells. The finding of functional PDGF receptors on human microvascular endothelial cells suggests an important direct role for PDGF in neovascularization.

Adipose Tissue↗
PubMed1991

Human microvascular endothelial cells express receptors for platelet-derived growth factor.

Endothelial cells have been widely thought to be unresponsive to platelet-derived growth factor (PDGF, a major growth factor released from stimulated platelets at the sites of vascular insults) and devoid of PDGF receptors. Nevertheless, in examining the growth-factor responses of microvascular endothelial cells isolated from human omental adipose tissue, we were surprised to detect PDGF-induced tyrosine phosphorylation of a 180-kDa glycoprotein, subsequently identified as the cellular receptor for PDGF by specific immunoprecipitation. Scatchard analysis of 125I-labeled PDGF binding to human microvascular endothelial cells revealed 30,000 PDGF receptors per cell with a Kd of 0.14 nM. PDGF stimulated tyrosine phosphorylation of PDGF receptors and other cellular proteins in a dose- and time-dependent manner, with half-maximal receptor phosphorylation occurring at 0.3 nM recombinant human PDGF (B chain) and a less than or equal to 1-min exposure to PDGF. Normal cellular consequences of receptor activation were also observed, including tyrosine phosphorylation of a 42-kDa protein and serine phosphorylation of ribosomal protein S6. Furthermore, PDGF was mitogenic for these cells. Microvascular endothelial cells play a central role in neovascularization required for wound healing and solid tumor growth. Thus, the discovery of functional PDGF receptors on human microvascular endothelial cells suggests a direct role for PDGF in this process.

Cell Division↗
PubMed1990

Actions of TNF and IFN-gamma on angiogenesis in vitro.

We have developed a model system for studying angiogenesis in which microvascular fragments and myofibroblasts (Mf) isolated from lipid tissues are grown in co-culture. We have found that Mf induce capillary formation by producing an endothelial cell growth factor and by secreting an extracellular matrix that causes endothelial cells to form a cordlike structure. This system appeared to be well suited for examining the effects of vasoactive substances such as the TNF and INF-gamma on capillary growth. TNF-alpha,beta, and IFN-gamma not only significantly inhibited capillary growth induced by Mf, but also blocked capillary development induced by fibroblast growth factors (FGF), well-known potent angiogenic factors. Recently, we have found that platelet-derived growth factor (PDGF) enhances in vitro capillary formation, probably at least in part by acting on Mf. Just as with FGF, capillary growth in the presence of PDGF was almost completely blocked by IFN-gamma. We examined the mode by which IFN-gamma inhibits angiogenesis and found that IFN-gamma inhibits both the proliferation of endothelial cells and collagen(s) synthesis by Mf. These actions of TNF or IFN-gamma could limit vascular formation in solid tumors.

Animals↗
PubMed1987

Platelet function in acute respiratory failure.

To assess the role of platelets in thrombohemorrhagic complications of acute respiratory failure (ARF), we studied platelet function in 13 ARF patients admitted for intensive care, in six acutely ill intensive care patients without evidence of acute lung injury (non-ARF), and in 10 normal subjects. Platelet counts in ARF and non-ARF patients were similar to the normal range. The bleeding time of the ARF patients (8.5 +/- 0.9 min) was significantly longer (p less than 0.01) than the normal (4.8 +/- 0.2 min) but similar to non-ARF patients (5.4 +/- 0.8 min). The bleeding time prolongations in ARF patients were unrelated to platelet concentration. Platelet aggregation induced by ADP and thrombin was normal in both ARF and non-ARF patient groups. The epinephrine response was impaired in one non-ARF patient and in three ARF patients; collagen-induced aggregation was absent in two ARF patients, with a prolonged bleeding time. Levels of VIII:C and vWF in both groups of patients were similar to the normal level, but VIIIR:Ag levels in ARF patients (407 +/- 45% of normal) were higher (p less than 0.01) than in both non-ARF patients (210% +/- 10%) and normal subjects (106% +/- 4). The electrophoretic mobility of VIIIR:Ag was abnormal in ARF patients. The prolonged bleeding time in ARF patients appears to result from the qualitative and quantitative VIIIR:Ag defect. beta-Thromboglobulin levels were greater (p less than 0.01) in ARF patients (87.6 +/- 6.9 ng/ml; p less than 0.001) than in non-ARF patients (46.2 +/- 3.1 ng/ml) or in normal subjects (25.3 +/- 2.5 ng/ml p less than 0.0001). However, platelet factor 4 plasma levels in ARF patients (18 +/- 1.6 ng/ml) did not differ from those in non-ARF patients (15.0 +/- 3.0 ng/ml), but both were significantly different from normal (6.1 +/- 0.8 ng/ml). Plasma thromboxane B2 (T X B2) levels were not different from normal values in either ARF or non-ARF patients, but 6-keto-PGF1 alpha levels were significantly reduced (p less than 0.01) in ARF patients (215 +/- 43 pg/ml) compared to normal values (381 +/- 34 pg/ml). Non-ARF patients had 6-keto-PGF1 alpha levels (285 +/- 111 pg/ml) midway between the normal values and those of ARF patients. Our results suggest that in vivo platelet activation occurs in ARF. ARF patients have quantitative and qualitative platelet defects that may contribute to thrombotic and hemorrhagic complications.

6-Ketoprostaglandin F1 alpha↗