Gene Therapy

Controlled delivery of EPO genes to humans is another approach for EPO therapy. Early work in this field depended on direct injection of plasmid DNA containing con-stitutively active EPO genes into the muscles of mice (146), resulting in a measurable increase in hematocrit. Several concerns became apparent from these studies, including inefficient and variable delivery of the EPO gene, with subsequent variations in EPO concentration. Although improvements in expression systems and better gene...

Future Directions

A number of chapters in this volume focus on current research that could lead to future clinical applications. Croker and Nicola review the pathways of cytokine signaling. These pathways when aberrant could be involved in oncogenesis, and thus an understanding of signaling may lead to new targets for the development of therapeutics. It is also possible that for some applications, targeting of the intracellular signaling pathway will lead to more selective and orally active stimulants of...

Humana Press

2004 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Due...

Therapy

The current recommendation for patients with early-stage CLL is that treatment should not be initiated without specific indications (i.e., symptomatic progression or a rapid lymphocyte doubling time). This recommendation is based on data demonstrating that currently available therapies do not cure patients with CLL, yet may be associated with significant toxicities (22). For patients with advanced disease, the most active classes of chemotherapy drugs are alkylating agents (chlorambucil and...

Conclusions

Although much can be learned about the cellular effects of HGFs from their activities in vitro, animal models have been indispensable for understanding the basic physiology of the HGFs. Loss-of-function models and overexpression models have particularly contributed to this understanding of physiologic roles. Animal studies are a mandatory part of the preclinical development of new biologic therapeutics, and many specific models of particular therapeutic scenarios have delineated the potential...

Introduction

Inbred laboratory mice with a particular constellation of traits including defective hematopoiesis, melanogenesis (pigmentation), and gametogenesis (fertility) have been studied since the 1930s (1-3). The molecular basis for these traits was uncovered with the findings in the late 1980s that the mutationally altered genetic loci in these mice, i.e., the W (dominant white spotting) locus or the Sl (steel) locus, correspond to the genes for the cell surface tyrosine kinase type receptor c-kit and...

Economic Analyses

To facilitate the comparison of different treatment strategies, economic outcome measures are often combined with clinical and HRQOL outcomes into summary measures such as QALY and cost-effectiveness (C E) and cost-utility (C U) ratios (34,35). Such combined summary outcome measures reflect the simultaneous difference or change in cost and the change in survival or quality-adjusted survival. When clinical effectiveness is not an issue or is considered equal between therapeutic alternatives, the...

Clinical Benefits of GCSF

The dangers of neutropenia are manifold, whether that neutropenia is iatrogenic or congenital in nature since neutrophils play a critical role in protecting the body against Comparison of Filgrastim and Pegfilgrastim No. of amino acids Cell source Glycosylation Pegylation C 75- g kg dose 5.5-1.8 for single 75- g kg dose 14.3-4.3 (0-24 h, ng h L ) for single 75- g kg dose 30- g kg dose 9.50-3.51 for single 30- g kg dose 887-336 (0-infinity, ng h L ) for single 30- g kg dose micro-organisms. The...

Hematopoietic Growth Factors And Mechanism Of Action

Before expanding on HGF antagonists, it is important to comment briefly on the native HGFs themselves and on how many of them work. HGFs are small glycosylated peptides of about 25,000-30,000 MW, many of which are also called cytokines or interleukins (ILs). They are produced by a variety of cells in the body and can act either locally or at a distance. In this review, we refer largely to antagonists of growth factors that operate on the hematopoietic system but also discuss those antagonists...

Limitations of Economic Analyses

The evaluation and interpretation of an economic analysis will often differ substantially depending on the perspective from which it was undertaken, e.g., the patient or family, a health care provider or institution, a third-party payor, or society as a whole. Indirect and intangible costs, although very important to the patient and family, may not be considered in economic analyses from most other perspectives. The analysis of economic outcomes is frequently complicated by the multiple...

Trial Objectives

These series of trials were designed to compare the safety, efficacy, and pharmacoki-netics of standard filgrastim administered daily with pegfilgrastim administered once per cycle. The primary endpoint was the duration of grade 4 neutropenia (days of severe neutropenia DSN ), defined as days the ANC was < 0.5 x 109 L during the first course of chemotherapy. The secondary endpoints were DSN in courses 2-4 the granulocyte profile and the time to ANC recovery defined as granulocytes > 2.0 x...

Hodgkins Disease

HD is the most common malignancy not considered an AIDS-defining condition in patients with HIV infection. The risk for developing HD in patients with HIV infection is approx 8.5 times higher than for patients without HIV infection (1). The adjusted incidence rate for HD has remained fairly steady during the 1990s in developed countries. The adjusted incidence rate was 0.5 per 1000 person-years from 1992 through 1996 and 0.4 per 1000 person-years from 1997 through 1999 (25). Unfortunately,...

Contents

1 Introduction to Hematopoietic Growth Factors A General Overview 3 2 Animal Models of Hematopoietic Growth Factor Perturbations in Physiology and 3 The Jak Stat Pathway of Cytokine 4 Small-Molecule and Peptide Agonists A Literature Part II. Hematopoietic Growth Factors 5 Granulocyte Colony-Stimulating 6 Erythropoietic Factors Clinical Pharmacology and Pharmacokinetics 97 Steven Elliott, Anne C. Heatherington, and MaryAnn Foote 7 Thrombopoietin 8 Stem Cell Factor and Its Receptor, 9...

Hematopoiesis Related Effects of SCF in Animals

Some in vivo studies with SCF have been mentioned above, in Subheadings 7.6.1., 7.6.2., 7.7., and 7.9. In general, preclinical in vivo studies with SCF have been done in mice, rats, dogs, and nonhuman primates with the species-homologous form of recombinant soluble SCF (4,5). Effects seen with respect to hematopoiesis have usually been reversible upon cessation of treatment. In Sl Sld mice, long-term administration of SCF brought about dose-related correction of the macrocytic anemia,...

Patient Response

Patient response to platelet transfusion varies. When data from patients with throm-bocytopenia undergoing hematopoietic progenitor cell transplantation were analyzed for platelet-corrected count increments after transfusion, a bell-shaped or polynomial distribution was found (Fig. 4), and patient-specific factors accounted for this distribution (42). Factors usually associated with response to platelets (e.g., history of previous transfusion, pregnancy, presence of HLA or platelet-specific...

Granulocyte Colony Stimulating Factor

CLL patients treated with fludarabine have been reported to have a significant incidence of severe infections (i.e., sepsis or pneumonia), especially in patients with advanced-stage disease or those who were pretreated (37). The incidence of severe infections ranged from 12 in previously untreated early-stage patients to 54 in previously treated advanced-stage patients. Grade 3 and 4 neutropenia were frequently reported and resulted in delays in therapy for approx 50 of the patients treated...

Successful Glycoengineering

Although rHuEPO has revolutionized the treatment of serious anemias and has been proved both safe and effective, its use is complicated by its relatively short physiologic half-life and the need for frequent, parenteral administrations. By using glycoengineering to introduce additional N-linked carbohydrate attachment points into rHuEPO, a new molecule was created with a prolonged serum half-life and increased vivo activity. Darbepoetin alfa (Aranesp ) is now available in the United States, the...

Pharmacodynamics Of rHuEPO

Erythropoietic responses to rHuEPO are generally measured by changes in reticu-locyte count, Hb concentration, and hematocrit (65). In an early study of healthy volunteers (65), the mean peak reticulocyte response occurred 4-5 d after a single intravenous dose of rHuEPO. In another study assessing multiple iv doses, 25 patients on hemodialysis received rHuEPO three times weekly at doses of 15, 50,150, or 500 U kg or placebo (111). Hematocrit values increased in a striking, dose-dependent...

RHuGMCSF and rHuGCSF

A study by Vadhan-Raj and colleagues (134) established that rHuGM-CSF could stimulate myelopoiesis in AA patients. rHuGM-CSF 60-500 g m2 was administered daily by continuous iv infusion for 2 wk followed by a 2-wk rest period in 10 patients with moderate-to-severe disease severity. White cell counts increased from 1.6- to 10fold, and neutrophil counts increased by 1.5- to 20-fold, with nine of the patients achieving neutrophil counts > 1.5 x 109 L. The median duration of treatment was 16 wk...

Keratinocyte Growth Factor

Keratinocyte growth factor (KGF), a member of the acidic fibroblast growth factor (FGF-7) family, is produced by fibroblasts and mesenchymal cells and acts on a wide range of epithelial-derived cells that express a unique splice variant of the FGFR2 receptor (119-122). Mice that are lacking either FGF-10 or FGFR2 splice variant have significant defects in thymopoiesis, hypoplastic thymic tissue, and impaired thymic epithelial cell development (121,123). Additionally, KGF has been shown to...

RHuGCSF

In a 6-8-wk dose-escalation phase 1-2 trial of subcutaneous (sc) rHuG-CSF at doses of 0.1-3.0 g kg d (39), 16 18 patients had an increase in the absolute neutrophil count (ANC) from 5- to 40-fold. Cessation of treatment resulted in return of counts to baseline values over a 2-4-wk period. Bone marrow myeloid maturation improved in 16 18 patients. No other significant lineage responses were noted. Eleven patients from this initial cohort were subsequently enrolled in a long-term maintenance...

Interleukin11

The preclinical studies of IL-11 effects in the context of myelotoxic or myeloabla-tive therapies have been comprehensively reviewed (112,113). Studies were conducted in syngeneic mouse transplant models and in mice given radiotherapy, or chemotherapy, or a combination of these. Some studies included assessment of impact on modeled infectious and bleeding complications (145). Exogenous IL-11 promoted hematopoietic recovery, including accelerated platelet recovery, but another beneficial effect...

TPO SB 394725 SB 497115 and Related Compounds

Scientists at Ligand and GlaxoSmithKline (GSK) developed a high-throughput, cell-based screen that detects activation of STAT in response to TPO. A large library of Fig. 3. Proliferative response of UT-7 TPO cells to TM41. UT TPO cells were deprived of growth factor for 24 h and then plated at a density of 2 X 104 cells well in Iscove's modified Dulbecco's medium (IMDM) containing 10 fetal calf serum (FCS) and incubated in the absence or presence of TM41 or thrombopoietin (TPO). After 3 d, the...

Aplastic Anemia and In Vitro Hematopoiesis

Quantitative deficits in the hematopoetic stem cell compartment are present in AA, exemplified by marked in vitro reductions in long-term culture-initiating cells or the number of hematopoietic progenitors by clonogenic studies (e.g., BFU-E, CFU-M, CFU-GM, CFU-MK) (110,111). Qualitative abnormalities of CD34 cells, such as Clinical Trials of Hematopoietic Growth Factors Used Alone in Patients With Aplastic Anemia Clinical Trials of Hematopoietic Growth Factors Used Alone in Patients With...

Assays For Erythropoietin

The earliest EPO assays were bioassays that measured biologic effects of the test sample in intact animals or cultures of erythroid tissues (1). Various endpoints were used, including 59Fe uptake, production of BFU-E or CFU-E, or increase in Hb concentration or reticulocyte number. Bioassays are still used as reference assays for establishing the potency of rHuEPO in pharmaceutical development. In vitro assays are useful in determination of receptor interactions and response at the cellular...

Granulocyte Macrophage Colony Stimulating Factor

Several studies report the effects of MuGM-CSF administration to mice for short periods (< 3 wk) (99,105), and one study assessed the effects of MuGM-CSF administration for 11 wk (106) (Table 9). A short course of MuGM-CSF administered either intravenously (99) or intraperitoneally (105) increased peripheral blood neutrophils only 1.5-2-fold, and the effects on myeloid kinetics were modest (99). GM-CSF had similar effects on bone morphology to those observed in G-CSF-treated mice, despite its...

Platelet Product Contamination

Estimated risk of sepsis related to apheresis platelets is 1 2000. This risk is greater with transfusions of pooled platelet concentrates from multiple donors. Because the risk of bacterial overgrowth increases with time, the shelf life of platelets stored at 20-24 C is limited to 5 d. The organisms implicated most commonly in fatalities, in descending order, are Staphylococcus aureus, Klebsiella pneumoniae, Serratia marcescens, and Staphylococcus epidermidis (6). Clinical presentation of...

Function

In a normal, healthy person, neutrophils are found almost exclusively in the blood and bone marrow. In the blood, some neutrophils flow in the central axial stream with erythrocytes, platelets, and other leukocytes. These neutrophils are described as being in the circulating pool. Other neutrophils are found rolling along the vascular endothe-lium. These neutrophils are described as being in the marginal pool. Neutrophils in the circulating pool are in a dynamic equilibrium with neutrophils in...

Kaposis Sarcoma

Kaposi's sarcoma, the most common malignancy in patients with HIV infection, occurs in 20-30 of patients (24). The incidence of Kaposi's sarcoma is 300-fold higher in patients with HIV infection compared with those without HIV infection (3). The adjusted incidence rate for Kaposi's sarcoma decreased from 15.2 per 1000 person-years from 1992 through 1996 to 4.9 per 1000 person-years from 1997 through 1999 in developed countries because of the administration of highly active antiretrovi-ral...

Economic Models Incorporating Indirect and Outof Pocket Costs

Limited information is available pertaining to direct nonmedical and indirect costs, which would provide a more societal perspective on the economic impact of neutrope-nia and CSF. A survey reported on 26 women with ovarian cancer experiencing severe or FN, including time lost from work for patients and caregivers and out-of-pocket expenses (80). All patients were recruited within 1 mo after the occurrence of grade 3 or 4 neutropenia. Resource utilization was tracked through a detailed...

EPO Mimetics

EPO mimetics are compounds that mimic the activity of EPO but bear no structural homology. EPO mimetics can have different biologic or biophysical properties from EPO that might allow a nonparenteral route of delivery. Significant challenges are associated with the identification and development of a useful EPO mimetic. First, the molecule must be small enough to be delivered orally (preferably < 600 Daltons) but large enough to retain full affinity for EPOR and to have an acceptable...

HIV Transmission

Transfusion-associated HIV infection was first reported in late 1982 and early 1983. HIV antibody testing was implemented in March 1985, and over the next 5 years, only about five cases of transfusion-associated HIV infection were reported annually. In the year before testing started, 714 cases were reported (7). In late 1995, blood banks began testing donors for p24 antigen to further decrease the risk of transfusion-transmitted HIV disease. In 1999, nucleic acid testing was introduced to...

Models to Predict Patients at Risk for Neutropenia and Patients Who Will Benefit From Prophylactic Pegfilgrastim

Appropriate stewardship of limited health care resources compels us to target therapies to prevent costly over utilization. The work of Silber et al. (32) was a good beginning. Development of more precise methods to target only those patients at risk for the complications of neutropenia is urgently needed. The cost of hospitalization for an episode of FN may more than offset the cost of prophylactic filgrastim or peg-filgrastim, however. The issues are complicated by competing priorities that...

References

Cytokine receptor dimerization and activation prospects for small molecule agonists. Bioorg Med Chem 2001 9 557-562. 2. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. Cytokine receptor signal transduction and the control of hematopoietic development. Annu Rev Cell Dev Biol 1996 12 91-128. 3. Frank SJ. Minireview receptor dimerization in GH and erythropoietin action. It takes two to tango, but how Endocrinology 2002 143 2-10. 4. Watowich SS....

Recommendations for the Use of White Blood Cell CSFs 231 Primary Administration

Prospective randomized trials showed that the primary administration of rHuG-CSF in standard-dose chemotherapy for SCLC reduces the severity and duration of neu-tropenia, leading to a lower incidence of FN (approx 50 lower). This result allows an increase in the number of courses of chemotherapy given on time. Treatment outcome was not the primary endpoint in these studies, but observed response and survival rates were similar in both cohorts of these trials. Because of cost constraints,...

Incidence of Anemia in Patients

The prevalence of pretreatment anemia varies across different solid tumor types. In an anemia audit, up to 60 of patients with lung cancer had Hb values < 11 g dL, a considerably higher prevalence than in patients with colorectal or breast cancer (10-20 ). Consequently, approx 40 of patients with lung cancer needed blood transfusions, compared with only about 20 of patients with breast cancer (16). The proportion of patients with anemia increases over the course of treatment. The problem of...

Threshold Dose in the Treatment of Breast Cancer

The Cancer and Leukemia Group B (CALGB) did a randomized trial evaluating different doses and dose intensities of adjuvant chemotherapy in patients with node-positive breast cancer 1572 patients were randomized to receive CAF at three dose levels low-dose (5-flurouracil 300 mg mL, doxorubicin 30 mg mL, cyclophosphamide 300 mg mL), moderate dose (5-fluorouracil 400 mg mL, doxorubicin 40 mg mL, cyclophosphamide 400 mg mL), and high dose (5-fluorouracil 600 mg mL, doxorubicin 60 mg mL,...

Granulocyte Colonystimulating Factor And Granulocytemacrophage Colonystimulating Factor For Chemotherapyinduced

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are endogenous glycoproteins that participate in the differentiation and proliferation of granulocytes, monocyte-macrophages, and other cells for hematopoeisis (17). Myelosuppresion is the major toxicity of chemotherapy for solid organ tumors, and prolonged myelosuppression and neutropenia lead to a reduction in chemotherapy dose intensity. Therefore, with the discovery, cloning, and...

Surgical Thrombocytopenia

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three thrombocytopenic, HIV-infected baboons were treated with three doses of PEG-rHuMGDF (arrows), and the platelet count was measured. (Reproduced with permission from ref. 96.) 20 -10 Fig. 10. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three...

Use in Increasing Chemotherapy Dose Intensity

The guidelines note that there is an apparent steep dose-response curve in preclinical studies but that retrospective analyses of dose-delivered intensity in the clinic suggest that bias may have been introduced. Some of the randomized trials compared lower than standard-dose chemotherapy with standard-dose chemotherapy. In the late 1990s, trials increasing dose intensity above standard levels were not shown to improve survival. The recommendation was that outside the setting of clinical...

Risk Factors for Chemotherapy Induced Febrile Neutropenia

Infection and inflammation stimulate release of endogenous cytokines (e.g., inter-leukin-1 IL-1 , tumor necrosis factor TNF , and IL-6) into the circulation. These cytokines reset the thermoregulatory center in the hypothalamus to retain heat and allow the core temperature of the body to increase. Mononuclear phagocytes are the principle producers of the endogenous cytokines that cause fever and are much less affected by chemotherapy than neutrophils. Therefore, fever is reliable as a marker of...

Colony Stimulating Factor Therapy

Results from randomized, controlled clinical trials demonstrate that filgrastim reduces the duration and severity of neutropenia after chemotherapy administration (10,44 see Table 2). Results from clinical trials demonstrate that rHuGM-CSF has a more limited effect than rHuG-CSF in decreasing the duration and severity of neu-tropenia after cancer chemotherapy administration (45-48). The incidence of FN and documented infections, use of antibiotics, and duration of hospitalization for FN are...

Dose Intensity in Breast Cancer Preclinical and Retrospective Clinical Data

Preclinical in vivo and in vitro data suggest that increasing the dose of chemotherapy increases tumor cell kill, but with significant myelosuppression (4). Hryniuk and Bush (5), in a literature review of regimens for metastatic breast cancer, calculated the dose of CMF chemotherapy given over a unit of time and concluded that a relationship was apparent with dose intensity and response rate in the setting of metastatic breast cancer. For the adjuvant setting, Hryniuk and Levine (6) evaluated...

Use Of Csfs For Wbc Support

Neutropenia is a common side effect of chemotherapy for lung cancer. Neutropenia can be associated with febrile neutropenia (FN), neutropenic sepsis, which may be life-threatening, prolonged hospital admission for administration of iv antibiotics, and increased cost. Grade and duration of neutropenia have been correlated with the risk of developing sepsis. The use of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) or rHu granulocyte-macrophage colony-stimulating factor...

Use Of Csfs For Rbc Support 11 Introduction

Anemia is a common clinical problem in patients with lung cancer. Many patients with lung cancer exhibit anemia at diagnosis that may be aggravated by disease-specific therapy, which is often platinum-based. Many patients with lung cancer are symptomatic (1). In these patients, anemia may cause or aggravate shortness of breath and fatigue. Fatigue is the most often reported symptom in cancer patients receiving chemotherapy and has profound consequences on quality of life (QOL) (2). Anemia can...

Expression Of Scf And cKit mRNAs

Expression of SCF and c-kit mRNAs in tissues of the mouse during embryogenesis and after birth has been thoroughly studied by in situ hybridization (38-41). A number of important results emerged from these studies 1. During embryogenesis, expression of the mRNAs first becomes apparent with the start of organogenesis about d 8.5, and the patterns of expression become increasingly more specialized as organogenesis proceeds. For hematopoiesis, the localization of expression of the mRNAs matches...

Post Transfusion Hepatitis

Labeling of blood from paid donors, a practice started in 1972, and the implementation of third-generation screening tests for hepatitis B surface antigen markedly reduced transfusion-transmitted hepatitis B but were found to eliminate only about 10 of all post-transfusion hepatitis cases by 1995 (6). Risk for non-A, non-B posttransfusion hepatitis was reduced when potential HIV-positive donors were excluded and was decreased again when donors were tested for the surrogate markers alanine...

Concurrent Use With Chemotherapy

In 1994, Livingston et al. (43) began a series of studies exploring the concept of dose density, namely, multifractioned doses of chemotherapy given at shorter intervals than standard regimens. To prevent dose-limiting myelosuppression, they began intermittent and then continuous neutrophil support with daily filgrastim. In the first study, vinorelbine 35 mg m2 was given weekly with continuous filgrastim 5 mg kg to 40 patients previously treated with anthracyclines and resistant to paclitaxel....

Nonsmall Cell Lung Cancer

The use of CSFs in induction chemotherapy for stage IIIA NSCLC has been restricted to reduction of the risk of neutropenia-related infections to avoid dose reductions or dose omissions. No randomized data to evaluate this approach are available. Some randomized trials focused on the role of high-dose or dose-intensive, cisplatin-based chemotherapy in stage IV NSCLC (Table 7). A very small phase 2 double-blind, placebo-controlled study compared chemotherapy with mitomycin C, vindesine, and...

Lung Cancer Treatment

EGF receptor regulates the growth of many types of cells. EGF receptor overexpression is common in lung cancer. The EGF receptor can be blocked by an Ab such as the human-chimeric MAb cetuximab that binds to its extracellular domain or by small molecules such as gefitinib, a reversible inhibitor of EGF receptor tyrosine kinase (94,99). In two large phase 2 trials of patients previously treated with chemotherapy for nonsmall-cell lung cancer (NSCLC), response rates of up to 19 were reported for...

The Gmcsf Antagonist E21R

The GM-CSF antagonist E21R was generated following directed substitution of residues along the GM-CSF molecule. Examination of regions of interaction between the cytokine and receptor suggested the appropriate region for mutagenesis. Substitution of the Glu21 of wild-type GM-CSF with an arginine highlighted the essential role of this residue for binding to the high-affinity receptor (Pc) but not the low-affinity receptor (P alone), indicating that Glu21 must be a critical Pc contact residue....

Causes of Anemia in Patients

Anemia in patients with lung cancer has a multifactorial etiology (6). Contributing factors are the anemia of chronic disorders, concomitant postobstructive respiratory infections, tumor-induced autoimmune hemolysis, and bone marrow invasion or dysfunction caused by the tumor. These patients can also have iron, folate, or vitamin B12 deficiency, as well as blood loss from tumor erosion. Endogenous EPO is of particular interest, since anemic cancer patients have been shown to have...

Effect of Anemia on Disease Outcome

A Hb concentration > 11.0 g dL was a significantly (p 0.001) favorable prognostic factor in a large retrospective analysis of 2531 patients with advanced NSCLC (67). The relationship between anemia and survival was examined in a review of 60 papers, 25 of which were about lung cancer (3). The relative risk of death of anemic patients with lung cancer increases by 19 (95 confidence interval (CI) 10-29). This effect is present regardless of whether the patients are treated with chemotherapy,...

Immune Response Considerations

The administration of medicinal recombinant proteins raises the potential that the human immune system will recognize these proteins as foreign (1). A number of factors From Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology Basic Science and Clinical Therapeutics Edited by G. Morstyn, M. A. Foote, and G. J. Lieschke Humana Press Inc., Totowa, NJ have been shown to either encourage or discourage immune assault. Oral or intravenous administration illicits weak immune...

Pharmacokinetics in Nephrology Patients Intravenous Administration

Most pharmacokinetic studies in this population have evaluated anemic patients receiving dialysis who were rHuEPO-naive. Few studies have been published in patients who retain some degree of kidney function. Since rHuEPO is a therapy for these patients, the studies are limited in their ability to investigate dose ranges or fixed dose regimens. In general, after intravenous administration, the pharmacokinetic properties of rHuEPO are nonlinear with respect to dose, with clearance being faster at...

Recommendations for the Use of Erythropoietic Factors

Anemia is a problem in up to 50-60 of patients with lung cancer, especially if they are treated with platinum-based chemotherapy. Despite its well-documented profound impact on QOL, many clinicians only treat with transfusion, once severe anemia (Hb concentration < 8 g dL) is present. Much evidence supports the use of rHuEPO for chemotherapy-induced anemia, if the Hb concentration decreases by < 10 g dL (79). Although recent data suggest that QOL may be preserved better if rHuEPO is started...

Molecular Basis Of Wand Sl Phenotypes

Numerous different W and Sl mutant mice have been studied, and many of the underlying mutations have now been characterized at the molecular level (6). W, the first dominant white spotting mutant described (in the early 1900s) (2), is now known to represent a null mutation affecting c-kit mRNA splicing such that the c-kit polypeptide lacks a transmembrane domain, is not expressed at the cell surface, and lacks kinase activity (4,6). Homozygous animals are severely affected with respect to...

Other Pharmacokinetic Issues Related to Nephrology Patients

Degree of Renal Dysfunction Most pharmacokinetic studies in the nephrology population have been conducted in patients receiving dialysis. In a study aimed at investigating the impact of varying degrees of renal dysfunction (range of creatinine clearances < 3 to > 80 mL min per 1.73 m2), Kindler et al. (81) administered epoetin beta at doses of 130-152 U kg iv in 10 previously untreated patients. They found no relationship between the degree of renal dysfunction and either terminal...

Thrombopoietin Increases Platelet Count in Healthy Humans

PEG-rHuMGDF has been given to healthy volunteers (99) and healthy apheresis donors (100-102). Treatment of apheresis donors with a single dose of PEG-rHuMGDF on d 1 produces a dose-dependent increase in the platelet count that begins on d 5 and peaks after 10-12 d (Fig. 11). A clear dose-response effect is seen. Compared with placebo-treated donors who had platelet counts of 225 x 109 L, donors treated with 1 or 3 g kg of PEG-rHuMGDF had median platelet counts of 336 x 109 L and 599 x 109 L,...

Cancer Drug Discovery and Development

Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Theapeutics in Cancer, edited by Alan M. Gewirtz, 2004 Cancer Chemoprevention, Volume 1 Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui-Jamali, 2004 Hematopoietic Growth Factors in Oncology Basic Science and Clinical Therapeutics, edited by George Morstyn, MaryAnn...

Current Status Of Peptide Agonists For Cytokine Receptors

Many recombinant cytokines are successfully marketed as drugs, including recombinant forms of human growth hormone (hGH), EPO, G-CSF, interferon (IFN)-a, IFN-P, interleukin (IL)-2, and IL-11 (44). Others are in late stages of clinical development. Scientists have been searching for smaller peptide cytokine agonists that mimic the activity of their larger counterparts to use as probes for understanding the detailed mechanisms of receptor activation. EPO mimetic peptide 1 (EMP1) was the first...

Erythropoietic Molecules With Changes in Stability or Receptor Binding Activity

Endogenous EPO activates the EPORs on precursor red cells through homodimer-ization, whereby two receptor binding sites on a single EPO molecule crosslink two receptors (135). The two binding sites on rHuEPO have different affinities, high (approx. 1 nM) and low (approx 10 pM) (10). Initial binding is to the high-affinity binding site, followed by homodimerization of the receptor by binding to the low-affin ity binding site (9). Compounds that bind through the high-affinity site but do not...

Neutropenia in the Treatment of Breast Cancer

Rahmann et al. (15) evaluated the incidence of febrile neutropenia ( FN) body temperature > 37.2 C and ANC < 1 x 109 L) in patients with metastatic breast cancer who received systemic chemotherapy. Twenty-three percent of patients developed FN the incidence of fever did not increase until the ANC was < 0.5 x 109 L. The risk of infection was not increased until the ANC was < 0.25 x 109 L FN occurred in patients with a poor performance status or during the first course of chemotherapy...

Treatment Of Chemotherapyinduced Febrile Neutropenia

The treatment of patients with chemotherapy-induced FN is multifactorial and includes not only antibiotic and CSF therapy but also supportive measures. Observational vigilance is an important aspect in the care of patients with chemotherapy-induced neutropenia there is no substitute for frequent observation and examination, particularly of the oropharynx, chest, and abdominal and perirectal areas. Frequent blood cell counts, blood cultures, and culture and examination of exudates and other...

Primary Prophylaxis

Gill and co-workers (33) determined the maximum tolerated dose of rHuGM-CSF administered in combination with doxorubicin, bleomycin, and vincristine (ABV) given every 14 d. Antiretroviral and myelosuppressive medications were discontinued 2 wk before study entry. Patients received ABV on d 1 and daily rHuGM-CSF 250 or 500 Mg m2 sc on d 2-12. The overall response rate was 67 , and the complete response rate was 17 . White blood cell counts increased similarly with both rHuGM-CSF doses....

Radiation Therapy

Nonhuman primates were treated with 700 cGy, 60Co gamma, total body irradiation (TBI) and then daily with PEG-rHuMGDF, MGDF, rHuG-CSF, a combination of PEG-rHuMGDF and rHuG-CSF, or placebo. Treatment with MGDF, PEG-rHuMGDF, or PEG-rHuMGDF plus rHuG-CSF significantly decreased the duration of thrombocy-topenia (platelet count < 20 x 109 L for 0.25, 0, or 0.5 d, respectively) and the severity of the platelet nadir (28, 43, and 30 x 109 L, respectively) compared with the controls (12.2-d...

The Efficacy of Therapeutic Colony Stimulating Factors

Despite the demonstrated efficacy of rHuG-CSF in prevention strategies, it is often administered only after hospitalization for FN. The clinical as well as economic value of these agents administered therapeutically after the onset of FN continues to be debated, however. In a double-blind, placebo-controlled trial, Maher and colleagues (73) found that rHuG-CSF reduced the risk of prolonged hospitalization (> 11 d) by 50 although the median number of days of hospitalization was unchanged....

Prospective Dose Intensity Trials for Breast Cancer

Tannock et al. (7) evaluated the dose-intensity concept in a prospective setting for patients with metastatic breast cancer. Patients were randomly assigned to receive two dose levels of CMF chemotherapy every 3 wk standard (cyclophosphamide 600 mg mL, methotrexate 40 mg mL, 5-fluorouracil 600 mg mL) and low dose (cyclophosphamide 300 mg mL, methotrexate 20 mg mL, 5-fluorouracil 300 mg mL). Response rates were higher for the standard-dose cohort (30 vs 11 , p 0.3), but there was no statistical...

Diagnosis

The diagnosis of CLL is most often made incidentally when lymphocytosis is observed in routine blood tests. CLL cells express pan-B antigens (HLA class II, CD19 and CD20) and activation antigens (CD5, CD23, CD25, and CD71), but not terminal differentiation antigens expressed by plasma cells (3). CLL cells have a restricted repertoire of VH1 genes (distinct from that of normal B cells) (4). The two major features that distinguish CLL cells from normal B cells are the expression of CD5 (a T-cell...

Solid Tumors

A major initiative in the control of solid tumors has been the advent of therapies targeted specifically to cancer cells. This succeeds the strategy of developing cytotoxic drugs that disrupt the DNA of any dividing cells, resulting in widespread normal tissue toxicity. New targets include proteins involved in cell-signaling pathways, antigens, or growth factor receptors on the cell surface. Targeted therapies already used in the treatment of solid tumors include the MAb trastuzumab in breast...

Categories Of Antagonists Based On Mode Of Action

Strategies to block biologic signals arising from HGF receptors generally attempt to prevent the assembly of an active ligand-receptor complex or to perturb the transduction of intracellular signaling events from an activated ligand-receptor complex (Fig. 1). Different types of receptor antagonists have been generated, depending on their target in the ligand-receptor complex, their mechanism of action, or their molecular nature. One type of HGF antagonist is represented by soluble receptors....

MUlMMM m 0101 o

The activation of hematopoietic growth factor (HGF) receptors is mediated by the ligand-induced homo- or heterodimerization of cell surface receptor chains, resulting in receptor phosphory-lation by intrinsic or associated kinases and the recruitment of a raft of accessory signaling molecules. A number of strategies have been devised that are able to perturb the receptor activation process and, as a consequence, inhibit signaling from the HGF receptors. The presence of HGF binding...

Role Of Erythropoietin In Erythropoiesis

In healthy individuals, red blood cell (RBC) production matches RBC loss. This remarkable homeostasis is controlled primarily by changes in rates of RBC formation through alterations in EPO concentrations. EPO regulates erythropoiesis by promoting the survival, proliferation, and differentiation of erythroid progenitors (28). Erythro-poiesis encompasses the orderly differentiation of pluripotent, hematopoietic stem cells to mature erythrocytes. Erythropoiesis occurs primarily in the bone marrow...

Biologic Outcome of Jak Stat Activation

Many of the biologic effects of cytokines are mediated by the Stat transcription factors. The Stat proteins are cytoplasmic proteins that are recruited to receptors and activated by tyrosine phosphorylation upon cytokine stimulation before translocating to the nucleus as dimers to initiate transcription of a wide range of genes (Fig. 3). This affects a plethora of cellular activities, as evidenced by the phenotype of mice deficient in Jaks and Stats. Despite the in vitro evidence suggesting a...

Gastrointestinal Stromal Tumors Treated With Imatinib

The success of the small molecule imatinib in gastrointestinal stromal tumors provides an outstanding example that the strategy of targeted therapies can be useful in solid tumors (97). Conventional systemic chemotherapy is ineffective in gastrointestinal stromal tumors. For example, the intense DMAP (dacarbazine, mitomycin, doxorubicin, and cisplatin) regimen plus rHuGM-CSF achieved a 1.8 objective response compared with a 61 response in other leiomyosarcomas in one comparative study (98). A...

Small Cell Lung Cancer

Given the systemic nature of SCLC, chemotherapy is the keystone in the treatment. Despite the high chemosensitivity of SCLC, with an objective response achieved in approx 80 of the patients, remission is in general short, and relapses are frequently chemoresistant. Treatment strategies to prolong remission have therefore dominated clinical trials for SCLC in the past decade. The use of alternating non-crossresistant chemotherapy, maintenance chemotherapy, or dose intensification strategies were...

Tpo Tm41

Kimura and coworkers (38) have reported that a small organic molecule, benzodi-azepinone TM41, competes with TPO for binding to the receptor's extracellular region. A library of benzodiazepinones was synthesized and screened (using HTS automation) against the soluble form of human c-Mpl containing the ECD of c-Mpl and the human immunoglobulin Fc region (MPL-IgG). Several compounds were identified as dose-dependent inhibitors of TPO binding to MPL-IgG, but only TM41 was active in a...

Effects of SCF on Primitive Progenitor Cells In Vitro

In liquid cultures of bone marrow-derived primitive progenitors (of varying purity), SCF alone generally does little more than maintain survival of c-kit+ cells identified as primitive progenitors by the criteria referred to in Subheadings 7.2. and 7.3. (4,5,7). However, along with various combinations of other relatively early-acting cytokines (such as interleukin IL -3, IL-6, or granulocyte-macrophage GM CSF), SCF can promote the expansion of such cells. Studies include assessments of bone...

Dose Finding Trial Design Patients and Methods

Eligible patients included those with high-risk stage II (as defined by the investigator, this usually included any or all of these features four or more positive nodes, HER-2 neu overexpressed or amplified, high-grade, high-proliferative rate, stage III, and stage IV disease patients who had received no or one regimen for metastatic disease independent of any adjuvant therapy if the total cumulative dose of doxorubicin did not exceed 240 mg m2. Exclusion criteria included progression on a...

Granulopoietic Growth Factors Myelopoietins Progenipoietin Pegleridistim And Pegfilgrastim

The granulopoietic cytokines rHuG-CSF and rHuGM-CSF remain the standard of treatment for cytotoxic therapy-induced neutropenia (63-67). Although effective in 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (days) Post Irradiation Fig. 6. Effects of promegapoietin (PMP)-la administration in four different schedules on peripheral blood platelets (PLT) in 600-cGy X-irradiated nonhuman primates. The PLT were observed before and after treatment with control protein (0.1 autologous serum, n 11), or...

Construction And Screening Of Smallmolecule And Peptide Libraries

Cloning of hematopoietic receptors has provided targets to screen small molecules and peptides for hematopoietic agonist (7) and antagonist (8) activity. By constructing compound libraries and using high-throughput automation, hundreds of thousands of small molecules and peptides have been screened against these targets to identify, and subsequently optimize, lead molecules. Although the techniques for constructing small-molecule and peptide libraries are very different, the same types of...

Economic Outcome Measures

The most important economic outcome of interest for clinical decision making and health policy formation is cumulative total cost, which considers both the activity level over time and unit costs (32,33). The activity level represents the amount of various resources used and the time expended in providing medical care. Unit costs represent the cost associated with each unit of activity. The major focus of such economic analyses relates to those resources and costs, which might differ between...

Principles of Small Molecule Library Construction

Small-molecule libraries usually comprise approx 106 organic compounds (molecular weights < 600 amu) that have been prepared by combinatorial and or traditional medicinal chemistry techniques (classic synthesis). Because both traditional chemistry and combinatorial chemistry offer distinct advantages, they frequently are combined. Libraries also may contain natural product extracts that are isolated from native environmental sources. Using traditional medicinal chemistry, one molecule at a...

Index

AIDS-related malignancy, 357-371 American Society of Clinical Oncology (ASCO), 7, 8, 211-216, 277, 293, 325,429,438 American Society of Hematology (ASH), 7, 8 Anemia, 101, 163, 174, 249, 250-261, 312313 aplastic, 86, 89, 163, 333-347 of chronic disease, 101, 111, 313 Antibiotics, 225-226, 228 Antibodies, monoclonal, 281, 314, 449 Aspergillus spp., 225 Cancer carcinoma, 213, 357, 458, breast, 213, 222, 285-307 cervical, 358, 365-367 lung,212,213,224,249-269,458 Candida spp., 235 Chemotherapy...

Tpo Af13948

Cwirla and coworkers (46) used several peptide library construction methods and covalent dimerization to produce AF13948, a 28-amino-acid peptide that was equipo-tent to the natural growth factor TPO in cell-based assays. Peptides that bind to TPOR were identified using both phage display and lac repressor display of random peptide libraries. Libraries were screened against the immobilized ECD of TPOR, and the resulting clones were categorized into two families and two subfamilies based on...

Evaluation of Small Molecule Agonists

Evidence that small molecules can function as cytokine mimetics by inducing receptor dimerization is provided by the aforementioned examples however, few reports indicate that small molecules are capable of disrupting protein-protein interactions (8). Furthermore, none of the small molecules reported to date have shown the established safety and specificity of the recombinant counterparts to the native proteins. One reason that the discovery of small-molecule cytokine receptor agonists has...

Pediatric Studies

Many studies of filgrastim administration after chemotherapy in children with acute leukemias or solid tumors have shown that the incidences of adverse events were similar in patients receiving placebo no drug or filgrastim. In our own study of patients with high-risk acute lymphoblastic leukemia comparing 121 chemotherapy cycles plus filgrastim and 137 control chemotherapy cycles, only one World Health Organization grade III vasculitis was considered to be attributed to filgrastim (2). This...

Wand Sl Phenotypes

Numerous W mutations, mostly spontaneous in origin, and numerous Sl mutations, both spontaneous and generated by irradiation, have been described in mice (1-4,6). The most severe of these mutations lead to extreme anemia and in utero or perinatal lethality. Mice with milder manifestations may be viable through adulthood and show varying degrees of the classic defects in hematopoiesis, melanogenesis, and gametoge-nesis. The range of W and Sl mutant phenotypes clearly indicates that c-kit and SCF...

Animal Models Of Hematopoietic Growth Factor Excess

Administration of an HGF to a normal animal superimposes an acute excess of circulating factor on otherwise normal hematopoiesis, potentially mimicking factor-driven emergency hematopoiesis. Numerous preclinical evaluations of this type have been done, and only some are summarized in this chapter. A particular advantage of this approach is its flexibility for comprehensive testing of the in vivo effects of combinations of multiple different factors, including enabling a range of scheduling...

Pharmacokinetics of GCSF

RHuG-CSF has been administered to patients intravenously (13,14), subcutaneously (63), and intramuscularly (64). In each case, the pharmacodynamic response, i.e., the neutrophil effect, is similar. Serum concentrations increase very quickly after intravenous infusion and peak within a matter of minutes at over 350 pg mL (13,14). Serum concentrations attained after subcutaneous administration also suggest a very rapid absorption (15). The clearance of rG-CSF from the body has been examined in...

IFNa

Systemic IFN-a (36-50 MU m2 d) produced responses in 18-46 of patients with Kaposi's sarcoma (1) combination IFN-a (1-10 MU d) and zidovudine produced responses in approx 40-50 of patients with Kaposi's sarcoma (26,27). The major dose-limiting toxicity for combination IFN-a-zidovudine therapy is myelosuppression. The use of HGF in combination with IFN-a and zidovudine for the treatment of Kaposi's sarcoma was evaluated in two published studies. Daily rHuGM-CSF 5 Mg kg sc as primary prophylaxis...

Stat6

Stat6 is required for the actions of IL-4 on B and T lymphocytes. Stat6-deficient B lymphocytes have low proliferative capacity in response to IL-4 and submitogenic doses of anti-IgM antibody. Upregulation of the major histocompatibility complex (MHC) class II, as well as the low-affinity IgE receptor CD23, was abolished in response to IL-4 in the absence of Stat6. In T lymphocytes, Stat6 was essential for IL-4-induced proliferation and CD4+ T-cell differentiation and production of Th2...

Future Developments

Various methods of delivery have been investigated for rHuG-CSF including nebu-lization (53), oral delivery for a pegylated derivative (46), and rectal delivery (54), though none of these forms are available for clinical use to date. Alternative molecular forms that interact with the G-CSF receptor have been suggested. A small-molecule drug that acts only on the murine receptor has been reported in addition to other molecular entities such as agonistic antibodies and mimetic peptides. It is not...

The Solution

CSFs have demonstrated efficacy when used prophylactically in numerous randomized controlled trials by reducing the risk of FN, the risk of documented infections, and the need for dose reductions and treatment delays. The efficacy of CSFs is evident in elderly patients with cancer and across a number of disease entities and treatment regimens. Although apparently less effective, CSFs appear to be active when administered therapeutically to patients with established FN by shortening the duration...

Assays for Functional Activity

In functional assays, compounds are screened against a cell line that has, for example, been engineered to respond to a cytokine-induced signaling event using a lightgenerating luciferase reporter (9). The cell line expresses the functional cytokine receptor of interest, and compounds that activate this receptor cause cells to emit light. Competitive binding assays identify compounds that bind to the receptor, whereas functional assays reveal compounds that initiate receptor activation, thereby...

Antibiotic Therapy

Patients with FN should receive empirical, broad-spectrum antibiotic therapy. Each episode of FN must be assumed to be a potentially serious bacterial infection. Ordinarily, each episode of FN should be treated with maximal doses of intravenous antibiotics while diagnostic studies are in progress. For most patients, a brief hospital stay is also important for observation and treatment because of difficulty in determining which patients have serious infections in the physician's office or...

Aplastic Anemia

Aplastic anemia (AA) is an acquired bone marrow stem cell disorder characterized by hypocellular bone marrows and variable degrees of pancytopenia. Morbidity and mortality are related to disease-associated cytopenias and primarily include infection and bleeding. Therapy has principally consisted of either immunosuppressive therapy with antithymocyte or antilymphocyte globulin (ATG ALG) and cyclosporine as single agents or in combination, or allogeneic bone marrow stem cell transplantation. Both...

Clinical Practice Guidelines

Ble of improving convenience and compliance with cancer treatment. Because of these rapid advances, it is essential that these practice guidelines be continually re-evaluated in the light of rapidly emerging data that are expanding awareness of the impact of neutropenia and its consequences on patients and their disease course as well as the ability of CSFs to improve short-term and long-term clinical, QOL, and economic outcomes in patients. The proper decision on whether to use CSF support...

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in Western countries. The annual incidence estimate from the American Cancer Society is for approx 7000 new cases in the United States in 2003. (This number suggests an apparent decline in incidence, but it may reflect an increased ability to distinguish CLL from other chronic lymphoid leukemias 1 .) CLL tends to be a disease of the elderly the median age at diagnosis is 62 yr, and only 15 of patients present at an...

Assays for Receptor Binding

Molecules must bind to the cytokine receptor before dimerization can occur. To screen for molecules that display receptor binding and to determine receptor-binding affinity, small-molecule and peptide libraries are screened against the immobilized extracellular domain (ECD) of a receptor or cells engineered to express the receptor. Molecules that demonstrate binding may be receptor antagonists. These molecules are devoid of intrinsic activity, but they block the response to the cytokine by...