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R L Dedrick

Publications and source records attributed to R L Dedrick.

At least 19 recordsLinked to original sources
PubMed1992

Carcinogenic potency of alkylating agents in rodents and humans.

Alkylating agents are known to produce second tumors in cancer patients treated for their primary cancer. Since therapeutic doses are high and the pharmacokinetics of the drugs are thoroughly studied, these agents provide a unique opportunity to compare intrinsic carcinogenic potency between experimental animals and humans. We have examined the carcinogenicity of melphalan, chlorambucil, and cyclophosphamide in causing leukemia in patients treated for cancer or polycythemia vera and lymphosarcoma in rats and mice. A good correlation among species is observed when the carcinogenic potency is based on the total lifetime exposure to active species derived from these drugs.

Animals↗
PubMed1992

A quantitative analysis of tumor specific monoclonal antibody uptake by human melanoma xenografts: effects of antibody immunological properties and tumor antigen expression levels.

The time-dependent (5 min-72 h) localization of 3 radiolabeled anti-melanoma monoclonal antibodies (MAbs 436, IND1, and 9.2.27) was studied in paired label experiments in small (4-12 mg) s.c. human melanoma xenografts (SK-MEL-2 and M21) in athymic nude mice. MAb 436 recognizes a Mr 125,000 cell surface melanoma-associated glycoprotein antigen (125 kDa-MAA); MAbs IND1 and 9.2.27 recognize a high molecular weight melanoma-associated antigen, but with equilibrium association constants differing by 2 orders of magnitude (10(8)-10(10) M-1). The two tumors were found to differ in their antigen expression levels and in both interstitial and vascular volumes. Accumulation of MAbs in both tumors was determined primarily by antigen expression levels and also by physiological factors such as vascular permeability and vascular volume; at the dose administered (20 micrograms/mouse), differences in MAb affinity among specific MAbs had minimal effect on accumulation. Quantitative flow cytometry measurements showed that antigen expression in vivo differed from that of cultured tumor cells. In vivo, expression of the Mr 125,000 MAA decreased by a factor of about 2.5 in both tumors. In contrast, the in vivo expression of the high molecular weight MAA decreased in M21 tumors but increased by 2.0-3.5-fold in SK-MEL-2 tumors. Data were analyzed using a three-compartment pharmacokinetic model (C. Sung et al., Cancer Res., 52:377-384, 1992) to provide plasma-to-tissue transport constants (k), the interstitial fluid flow rate (L), and estimates of the in vivo interstitial MAb binding site concentration (B0). For all MAbs, the plasma-to-tissue transport constants were consistently greater for M21 tumors (0.44-0.85 microliter/min/g) than for SK-MEL-2 tumors (0.28-0.66 microliter/min/g), and values of k for both tumors were approximately 1 order of magnitude greater than those for skeletal muscle (0.06-0.08 microliter/min/g). The model-estimated binding site concentration of melanoma-specific antibodies was 15-70 times lower than that predicted by experimental measurements of tumor antigen concentrations. Factors that may contribute to this discrepancy include inaccessibility of tumor cell binding sites to MAb and MAb catabolism. In summary, these results indicate that, for the MAb dose used in this study, variables pertaining to the tumor target (i.e., antigen expression levels, vascular volume, and vascular permeability) are the most important for determining MAb accumulation in tumors.

Animals↗
PubMed1992

Predicted and observed effects of antibody affinity and antigen density on monoclonal antibody uptake in solid tumors.

The uptake and binding of monoclonal antibodies (MAbs) in solid tumors after a bolus i.v. injection are described using a compartmental pharmacokinetic model. The model assumes that MAb permeates into tumor unidirectionally from plasma across capillaries and clears from tumor by interstitial fluid flow and that interstitial antibody-antigen interactions are characterized by the Langmuir isotherm for reversible, saturable binding. Typical values for plasma clearance and tumor capillary permeability of a MAb and for interstitial fluid flow and interstitial volume fraction of a solid tumor were used to simulate the uptake of MAbs at various values of the binding affinity or antigen density for a range of MAb doses. The model indicates that at low doses, an increase in binding affinity may lead to an increase in MAb uptake. On the other hand, at doses approaching saturation of antigen or when uptake is permeation limited, an increase in the binding affinity from moderate to high affinity will have only a small effect on increasing MAb uptake. The model also predicts that an increase in antigen density will greatly increase MAb uptake when uptake is not permeation limited. Our experiments on MAb uptake in melanoma tumors in athymic mice after injection of 20 micrograms MAb (initial plasma concentration, about 120 nM) are consistent with these model-based conclusions. Two MAbs differing in affinity by more than 2 orders of magnitude (3.8 x 10(8) M-1 and 5 x 10(10) M-1) but with similar in vivo antigen densities in M21 melanoma attained similar concentrations in the tumor. Two MAbs of similar affinity but having a 3-fold difference in in vivo antigen density in SK-MEL-2 melanoma showed that the MAb targeted to the more highly expressed antigen attained a higher MAb concentration. We also discuss the model predictions in relation to other experiments reported in the literature. The theoretical and experimental findings suggest that, for high dose applications, efforts to increase MAb uptake in a tumor should emphasize the identification of an abundantly expressed antigen on tumor cells more than the selection of a very high affinity MAb.

Animals↗
PubMed1992

Quantitative examination of tissue concentration profiles associated with microdialysis.

Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate-putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extraction fraction over time were followed in vivo and in a simple in vitro system consisting of 0.5% agarose. These experimental results were then compared with mathematical simulations of microdialysis in vitro and in vivo. Simulations of in vitro microdialysis agreed well with experimental results. In vivo, the autoradiograms of the tissue concentration profiles showed clear evidence of substantial differences between 14 and 61.5 min, even though the change in extraction fraction was relatively small over that period. Comparison with simulated results showed that the model substantially underpredicted the observed extraction fraction and overall amount of sucrose in the tissue. A sensitivity analysis of the various model parameters suggested a tissue extracellular volume fraction of approximately 40% following probe implantation. We conclude that the injury from probe insertion initially causes disruption of the blood-brain barrier in the vicinity of the probe, and this disruption leads to an influx of water and plasma constituents, causing a vasogenic edema.

Animals↗
PubMed1992

Bidirectional peritoneal transport of immunoglobulin in rats: compartmental kinetics.

Protein transport to and from fluid in the peritoneal cavity is observed during clinical procedures. Dialysate osmolality is a major determinant of net fluid flux into the cavity. We carried out experiments in rats to determine the plasma, peritoneal, and tissue concentrations of immunoglobulin (Ig) G resulting from either intravenous (iv) or intraperitoneal (ip) administration during hypertonic or isotonic dialyses. After iv injection of IgG, overall mass transfer into the cavity was not affected by the osmolality. After ip injection, tissue concentrations were dependent on the dialysis duration. Protein absorption from the hypertonic dialysate into the surrounding tissue was quantitatively less than the absorption from an isotonic dialysis solution at 20 min. By 200 min, total protein transport was not affected by dialysate osmolality. Lymphatic transport to the plasma amounted to 20-25% of the total protein loss from the peritoneal cavity; approximately 60% of the absorbed dose was found in tissues surrounding the cavity at both 20 and 200 min, with particularly high concentrations in parietal areas. We conclude that immunoglobulin transport in the peritoneal tissue, resulting from either iv or ip injection, is influenced by route of administration but is little affected by dialysate osmolality. Peritoneal absorption of proteins occurs directly into the surrounding tissue interstitial space as a result of hydrostatic pressure-driven convection and diffusion.

Absorption↗
PubMed1992

Bidirectional peritoneal transport of immunoglobulin in rats: tissue concentration profiles.

Protein transport occurs between the blood and the peritoneal cavity during clinical procedures, but events within the surrounding tissue space are poorly understood. We used quantitative autoradiography to examine the tissue concentration profiles of immunoglobulin G (IgG) in regions surrounding the peritoneal cavity. We have varied the route of administration (intravenous or intraperitoneal), the osmolality of the dialysis solution (isotonic or hypertonic), and the time of analysis (20 or 200 min). After intravenous injection, IgG profiles were relatively flat in most tissues and were not affected by time or osmolality. Concentrations corresponded to the capillary density in specific tissues. After intraperitoneal administration, the IgG tissue profiles were significantly steeper than after intravenous administration. The tissue concentrations increased with time but decreased when a hypertonic solution was substituted for an isotonic solution. Hypertonic dialysis causes a water flux into the cavity, which dilutes the contents but does not prevent penetration of protein into the surrounding tissue. Based on IgG movement in tissue during hypertonic dialysis, the peritoneum appears to function as a heterogeneous structure, which allows osmotically induced water transport into the cavity in some regions with simultaneous transport of hydrostatic pressure-driven water and solute flow from the cavity into the tissue in other regions.

Animals↗
PubMed1991

Quantitative microdialysis: analysis of transients and application to pharmacokinetics in brain.

The behavior of a microdialysis probe in vivo is mathematically described. A diffusion-reaction model is developed that not only accounts for transport of substances through tissues and probe membranes but also accounts for transport across the microvasculature and metabolism. Time-dependent equations are presented both for the effluent microdialysate concentration and for concentration profiles about the probe. The analysis applies either to measuring the tissue pharmacokinetics of drugs administered systemically, or for sampling of endogenously produced substances from tissue. In addition, an expression is developed for the transient concentration about the probe when it is used as an infusion device. All mathematical expressions are found to be a sum of an algebraic and an integral term. Theoretical prediction of time-dependent probe behavior in brain has been compared with experimental data for acetaminophen administered at 15 mg/kg to rats by intravenous bolus. Plasma and whole striatal tissue samples were used to describe plasma kinetics and to estimate a capillary permeability-area product of 0.07 min-1. Theoretical prediction of transient effluent dialysate concentrations exhibited close agreement with experimental data over 60 min. Terminal decline of the dialysate effluent concentration was slightly overestimated but theoretical concentrations still lay within the 95% confidence interval of the experimental data at 112 min. Microvasculature transport and metabolism play major roles in determining microdialysate transient responses. Extraction fraction (recovery) has been shown to be a declining function in time for five probe operating conditions. High rates of metabolism and/or capillary transport affect the time required to approach steady-state extraction, shortening the time as the rates increase. Conversely, for substances characterized by low permeabilities and negligible metabolism, experimental situations exist that are predicted to have very slow approaches to microdialysis steady state.

Acetaminophen↗
PubMed1991

Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration.

Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin, 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans, and if so, if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery, while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions, a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.

Analysis of Variance↗
PubMed1990

Pharmacokinetic analysis of immunotoxin uptake in solid tumors: role of plasma kinetics, capillary permeability, and binding.

The delivery of cell-specific protein toxins to the interstitium of solid tumors was examined in athymic mice bearing s.c. human rhabdomyosarcoma (TE671) tumors. The toxins are diphtheria toxin (DT), Mr = 60,000, and an immunotoxin, Mr = 210,000. The immunotoxin is a chemical conjugate of a mutant DT defective in binding and a monoclonal antibody specific for the human transferrin receptor. The plasma, tumor, and muscle concentrations of DT, immunotoxin, and closely related nonbinding controls were measured 2, 6, and 24 h after i.v. injection into tumor-bearing mice. Both DT and immunotoxin are specific for the human xenograft in the mouse because DT is very toxic to human cells but not to murine cells and immunotoxin is directed against a human cell receptor. A compartmental pharmacokinetic model was developed for the analysis of the in vivo data to provide plasma-to-tissue transport constants (capillary permeability-area products), binding parameters (products of the association constant and the initial binding site concentration), and the interstitial fluid flow rate. The model also provides a simple mathematical framework for understanding the effect of these variables on the localization of macromolecules in tumors. The plasma-to-tissue transport constant of immunotoxin in TE671 tumor was 0.13 microliters/min/g, compared to 0.29 microliters/min/g for DT. However, despite the lower capillary permeability of the larger molecular weight toxin, the cumulative tumor exposure to immunotoxin was 80% higher than that to DT after 24 h. A longer plasma half-life and higher apparent in vivo binding parameter of immunotoxin compared to DT contributed to the higher tumor exposure. Plasma-to-tissue transport constants for tumor were 60 to 100% higher than those for muscle. This finding is consistent with observations by others that tumor vasculature is more permeable than are normal muscle capillaries. Also, the interstitial fluid flow of the tumor, 0.80 microliters/min/g, was higher than that of muscle, 0.58 microliters/min/g. The product of the binding affinity and binding site concentration for immunotoxin in vivo was 530 times lower than that predicted based on in vitro measurements. Lower expression of antigen binding sites, inaccessibility of binding sites in vivo, and degradation of the toxin are several possible factors that may account for the in vitro-in vivo differences in binding. This study illustrates the interrelationship of plasma kinetics, capillary permeability, and binding and their effects on toxin concentrations that are achieved in the tissue interstitium.

Animals↗
PubMed1990

cis-acting sequences required for class II gene regulation by interferon gamma and tumor necrosis factor alpha in a murine macrophage cell line.

In this report, we have demonstrated that IFN-gamma and TNF-alpha increase expression of both the I-A and I-E region gene products on the surface of the myelomonocytic cell line WEHI-3, and that they mediate this increase via an increase in A alpha transcription. Constructs containing 5' deletion mutations of the A alpha promoter attached to the bacterial chloramphenicol acetyl transferase gene were used to delineate the minimum 5' flanking sequences required for promoter activity, and for inducibility by IFN-gamma and TNF-alpha. Approximately 115 bp of 5' sequences are required for minimum induction by IFN-gamma or TNF-alpha when the cytokines are present separately. This includes the three conserved promoter elements, the X, Y, and H boxes. Nested linker-scanner mutations demonstrated that additional regions were also critical for optimal induction by IFN-gamma or TNF-alpha. These include the kappa B-like enhancer and a TNF-alpha-specific sequence that we have tentatively called the T box. The T box sequence was also found in the promoter regions of the human HLA-DQ alpha and rat RT1.B alpha genes. Although the entire T box sequence element was not found in the other mouse class II genes, all class II alpha genes contained the SV40 core enhancer element in the regions included by the T box. Mouse class II beta genes appear to contain neither the T box nor the core enhancer element in this region, suggesting differential regulation of class II alpha and beta genes by TNF-alpha.

Animals↗
PubMed1990

Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro.

A mathematical framework was developed to provide a quantitative basis for either in vivo tissue or in vitro microdialysis. Established physiological and mass transport principles were employed to obtain explicit expressions relating dialysate concentration to tissue extracellular concentration for in vivo applications or external medium concentrations for in vitro probe characterization. Some of the important generalizations derived from the modeling framework are: (i) the microdialysis probe can perturb the spatial concentration profile of the substance of interest for a considerable distance from the probe, (ii) for low molecular weight species the tissue is generally more important than the probe membrane in determining the dialysate-to-tissue concentration relationship, (iii) metabolism, intracellular-extracellular and extracellular-microvascular exchange, together with diffusion, determine the role of the tissue in in vivo probe behavior, and, consequently, (iv) in vitro "calibration" procedures could be useful for characterizing the probe, if properly controlled, but have limited applicability to in vivo performance. The validity of the proposed quantitative approach is illustrated by the good agreement obtained between the predictions of a model developed for tritiated water ([3]H2O) in the brain and experimental data taken from the literature for measurements in the caudoputamen of rats. The importance of metabolism and efflux to the microvasculature is illustrated by the wide variation in predicted tissue concentration profiles among [3]H2O, sucrose and dihydroxyphenylacetic acid (DOPAC).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Sequence elements required for activity of a murine major histocompatibility complex class II promoter bind common and cell-type-specific nuclear factors.

We have examined the sequence elements and corresponding DNA-binding factors required for transient expression of the A alpha d promoter fused to the bacterial chloramphenicol acetyltransferase reporter gene in a variety of cultured cell lines. Deletion analysis demonstrated that only about 110 nucleotides of sequence 5' of the transcription start site are required for constitutive expression in the murine B-lymphoma cell line A20 or for gamma interferon-induced expression in the murine monocytic cell line WEHI-3. Linker-scanner mutation of this region indicated that at least three sequence elements are required for promoter activity. These elements correspond to the conserved sequence elements found in other human and mouse class II genes, the X box, the Y box, and the H box. Analysis of DNA-binding activity showed that the three most predominant factors present in extracts from WEHI-3, A20, or L cells (which do not express the class II genes) are actually a family of factors that bind to a fourth sequence element, overlapping the 3' end of the X-box sequence, that is homologous to the cyclic AMP-responsive enhancer element. A single common factor that binds to the Y box was detected in extracts from all cells tested, as has been seen with the Y-box elements of other class II genes. Another common factor was found that binds to the more conserved 5' region of the X-box element, although A20 extracts contained a second, distinct binding activity for this region. A common binding factor for the H-box element was detected in extracts from WEHI-3 and L cells. However, this activity was absent in A20 cell extracts. Instead, two different H-box-binding activities were detected, suggesting that different components are involved in class II gene expression in B cells and macrophages. Finally, gamma interferon treatment did not significantly alter the DNA-binding activity in WEHI-3 cells for any of the sequence elements shown to be required for induced chloramphenicol acetyltransferase expression.

Animals↗
PubMed1990

Diphtheria toxin effects on brain-tumor xenografts. Implications for protein-based brain-tumor chemotherapy.

A model was developed to determine whether protein-based chemotherapeutic agents can cross the blood-brain barrier and successfully treat brain tumors. The human small-cell lung carcinoma N417D was grown as a solid tumor in the nude rat brain, and diphtheria toxin (DT) was administered intravenously as therapy. Because rat cells lack functional DT receptors and are 1000 to 10,000 times less sensitive to DT than human cells, a therapeutic window exists between the implanted human tumor and the nude rat host. The pharmacokinetic and pharmacodynamic characteristics of DT were defined. Within 6 hours, more than 90% of the initial DT concentration was removed from the blood. The blood-to-tumor transfer constant Ki for DT in small N417D tumors was 0.49 microliters/gm-min, one-fourth to one-fifth the reported values for permeability to proteins in other experimental tumor models. Despite the toxin's short plasma half-life and the relatively intact blood-tumor barrier, DT administered intravenously as a single dose significantly extended animal survival. Untreated nude rats developed solid parenchymal tumors and died in 11 to 16 days (median 15 days). When administered at 0.1 micrograms/animal, DT increased the median survival time to 19 days (p less than 0.0016) while 1.0-microgram doses extended median survival times to 26.5 days (p less than 0.0002). A higher dose of DT (3.0 micrograms) had no further beneficial effect on survival (26.1 days). Blood-brain barrier constraints to successful monoclonal antibody-based therapies of brain tumors may have been overestimated since antibody conjugates have plasma half-lives longer than DT, and the permeability of N417D tumors to DT is equal to or less than the permeability of other experimental tumors to large proteins. Recently developed immunotoxins that have the higher potency of DT and a therapeutic window as wide as DT has in this nude rat/human tumor paradigm may be effective in treating brain tumors despite limited blood-tumor permeability.

Animals↗
PubMed1989

Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II).

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supra-additive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity. The demonstration of true supra-additive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supra-additive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supra-additive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Arterial drug infusion: pharmacokinetic problems and pitfalls.

The pharmacokinetic theory of intra-arterial drug administration has been clearly articulated. It provides a useful guide to the development and interpretation of preclinical studies and clinical trials. Despite the clarity and usefulness of the theory, there are misunderstandings of its implications and technical problems associated with its implementation. Few studies have been properly designed to validate the theory experimentally. Independence of steady-state pharmacokinetic advantage on intraregion blood flow differences predicted for a nonextracted drug is counterintuitive. Extrapolation from laboratory animals to humans raises some important questions of allometry, particularly for the brain, which does not follow the scaling rules applicable to other organs. Finally, drug streaming from the site of infusion has been observed in vitro and in vivo. The extent of the resulting clinical problem has not been adequately characterized, but it may be severe under some circumstances.

Animals↗
PubMed1988

Cisplatin pharmacokinetics: applications of a physiological model.

A physiological pharmacokinetic model for the disposition of the antineoplastic drug cis-diamminedichloroplatinum(II) (cisplatin or DDP) in several mammalian species is reviewed. The significance of the model's key parameters and of their interspecies relationships is discussed. Methods for estimating two of these parameters (the rate constants for formation of the fixed and mobile metabolites) from in vitro experiments are presented. Fixed and mobile metabolites are formed by the irreversible binding of cisplatin to macromolecules and low molecular weight nucleophiles, respectively. Use of the model to simulate and predict the pharmacokinetic behavior of cisplatin and its metabolites in different animal species following intravenous and intraperitoneal administration is illustrated. Fixed metabolite formation rate constants can be used in conjunction with mass transport parameters to estimate tissue exposures to cisplatin following systemic or regional drug administration. The model logically can serve as the basis for a pharmacodynamic model that incorporates cisplatin reactions with DNA. The model also provides a means for comparing the pharmacokinetic characteristics of cisplatin analogs and for assisting in rational analog development.

Animals↗