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Antineoplastic Agents and the Associated Myelosuppressive Effects: A Review

Jason N. Barreto, Kristen B. McCullough, Lauren L. Ice and Judith A. Smith
Journal of Pharmacy Practice 2014 27: 440 originally published online 20 August 2014
DOI: 10.1177/0897190014546108

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Drug-Induced Diseases
Journal of Pharmacy Practice
2014, Vol. 27(5) 440-446
Antineoplastic Agents and the Associated ª The Author(s) 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
Myelosuppressive Effects: A Review DOI: 10.1177/0897190014546108
jpp.sagepub.com

Jason N. Barreto, PharmD, BCPS1,

Kristen B. McCullough, PharmD, BCPS, BCOP1,
Lauren L. Ice, PharmD1, and
Judith A. Smith, PharmD, BCOP, CPHQ, FCCP, FISOPP2

Abstract
Bone marrow is a complex organ responsible for the regulation of hematopoietic cell distribution throughout the human body.
Patients receiving antineoplastic agents as a therapeutic intervention for hematologic malignancy often experience varying
degrees of myelotoxicity. Antineoplastic agents cause hypocellularity in marrow resulting in a reduction in hematopoietic tissue
activity and a corresponding decline in cell production. Quantifying the adverse effects on hematopoiesis is based on the
properties of a single agent, the use of individual drugs within a combination chemotherapy regimen, and the course, or
courses, of chemotherapy designed to treat cancer. The direct or indirect suppression of erythrocytes, granulocytes, and
megakaryocytes has potential for multiple negative clinical consequences ranging from increased monitoring of blood counts to
life-threatening infection and death. This review will provide an overview of the structure and function of competent adult bone
marrow, describe the process of hematopoiesis, and characterize the myelotoxicities associated with common antineoplastic
agents currently used in the treatment of cancer.

Keywords
antineoplastic agents, chemotherapy, myelosuppression, toxicity, cancer, oncology, hematology, thrombocytopenia, neutropenia,
anemia

Introduction induced hematologic toxicity. This will build a foundation for

The utilization of antineoplastic agents alone or in combination
is a balance between administering a therapy designed to com-
bat malignancy and the propensity for that therapy to cause the
frequently occurring, clinically important consequence of
hematopoietic disruption. Although hematologic toxicities are
fairly common with antineoplastic treatment, it remains diffi-
cult to predict susceptibility and severity of these toxicities in
each patient.
Major advancements have been made over recent years;
however, chemotherapy-induced myelotoxicity remains one
of the primary causes of morbidity and mortality during the
treatment of cancer.1 Patients experiencing profound myelo-
suppression are at increased risk of chemotherapy-related
adverse effects. Antineoplastic-induced myelotoxicity can be
a major contributor to fatigue leading to an inability to perform
routine activities of daily living.2 Other more severe adverse
effects include bleeding events or life-threatening infection
manifesting as febrile neutropenia and sepsis.3,4
This review will provide an overview of normal bone marrow
physiology, cell cycle progression, and hematopoiesis. Current
antineoplastic agents and treatment regimens will also be dis-
cussed to provide insight into the complexities of chemotherapy-
considering the interventions that can be employed as prevention
and treatment of dose-limiting hematologic toxicities in the clin-
ical setting.
Bone Marrow
Comprehension of antineoplastic-induced myelotoxicity begins
with understanding the impact of antineoplastics on the struc-
ture and function of normal, competent, adult bone marrow.
Bone marrow is one of the most complex systems of the body,
ranging from a weight of 2600 g to up to 5% of body weight in
humans, and approximately half is assumed to be actively par-
ticipating in blood cell formation at any one point in time.5-8
1
Department of Pharmacy Services, Mayo Clinic, Rochester, MN, USA
2
Department of Gynecologic Oncology & Reproductive Medicine, Division of
Surgery, The University of Texas M.D. Anderson Cancer Center, Houston,
TX, USA
Corresponding Author:
Jason N. Barreto, Department of Pharmacy Services, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905, USA.
Email: barreto.jason@mayo.edu

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Barreto et al
Surrounded by dense cortical bone is a medullary cavity that con-
sists of trabecular bone and bone marrow tissue. Bone marrow can
be divided into 2 types and classified by the cellular composition
and color. Red marrow is a fibrous, myeloid tissue that is depos-
ited within the cavity including the ends of long bones and is the
primary site of hematopoiesis. The red marrow can be further
classified into intravascular and extravascular compartments with
the former composed of arteries responsible for the blood supply
providing nutrients and a network of thin-walled venous blood
vessels commonly referred to as sinuses. These sinuses are
responsible for transporting blood cells away from the bone into
circulation. Myelinated and nonmyelinated nerve fibers accom-
pany the vasculature and inundate the marrow ultimately control-
ling the retention and migration of cells.5,6,9 The extravascular
compartment is where the process of hematopoiesis occurs and
formed blood cells are stored.24,25 These compartments are sepa-
rate anatomical units, called microenvironment, that are con-
nected by a network of fenestrated capillaries and mesh of
connective tissues with walls composed of endothelial and adven-
titial reticular cells.7,9
Marrow tissue is a living organism possessing a finite life
span that will experience a decline in functional capacity in
direct correlation with age.10 All bone cavities are filled with
hematopoietic cells at birth reflecting a uniformly red marrow.
With increasing age, hematopoietic tissue ceases proliferative
activity and transforms into a spongy adipose tissue and
becomes yellow marrow. The gradual, centrifugal replacement
of red marrow with yellow leaves approximately 50% of the
original marrow actively proliferating by adulthood with the
continued remodeling leaving less than one-third in advanced
ages. Interestingly, the body has the capability to convert yel-
low marrow into red marrow to accommodate situations requir-
ing increased cell production such as stress of disease and
administration of chemotherapy.1,9
The marrow is capable of producing and releasing an
average 6 billion cells/kg of body weight per day into circu-
lation, divided into 2.5 billion erythrocytes, 1.0 billion gran-
ulocytes, and 2.5 billion platelets per kilogram of body
weight per day.1,5,6 It is important to note that blood cell
production is a dynamic process and the body can downre-
gulate to near inactivity or upregulate to 5 to 10 times con-
ventional production to maintain the balance of steady-state
conditions.7,8
The Cell Cycle
Cells are living entities also with a finite life span. Our know-
ledge of cell and cell division has grown tremendously since
the discovery of mitosis in 1882.11 The concept of a cell under-
going a cyclical pattern of events was introduced to the scien-
tific community in 1953 and is the foundation of cell biology.12
The cell cycle is the fundamental process through which cells
proliferate and is comprised of 2 principle operations,
DNA replication and mitosis.13-16 It is a highly regulated and
ordered activity involving GAP1 (G1-phase), Synthesis
(S-phase), GAP2 (G2-phase), and Mitosis (M-phase) as shown
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441
in Figure 1.12,14,16-18 During the G1-phase, cells prepare for and
commit to DNA synthesis. DNA replication takes place during
the S-phase. Following the S-phase, cells prepare for cell divi-
sion in the G2-phase. Finally, nuclear division and separation
transpires during the M-phase resulting in 2 identical progeny
cells.14,16,17 Before committing to replication, cells in the
G1-phase can enter a quiescent stage called G0 due to a lack
of mitogenic signals or the presence of antimitogenic signals.14,16
A high percentage of cells in the body exist in phase G0.13,18
Cellular division is moderated by numerous protein families
that regulate transition from one stage to the next in a systema-
tic fashion.15,16 Checkpoints in the cycle exist to certify the
integrity of the cycle and ensure DNA is maintained.16,17 A key
difference between normal and malignant cells is control of cell
division. Mutations affecting regulation of division resulting in
uncontrolled cell proliferation are a foundation of malignant
states.16,19 Most antineoplastic agents consequently act on
molecular targets essential to cellular division. These agents
can have activity limited to specific phases or remain active
throughout the cell cycle (figure 1).
Hematopoiesis
Hematopoiesis is the production of blood cells within the bone
marrow.1,5,6,20 Despite the heterogeneity of blood cell types,
with each type having distinct functions and unique turnover
kinetics, the human body is able to maintain consistent levels
in the peripheral circulation.21,22 Hematopoiesis most often
occurs in the central or extravascular compartment with the
ability to take place in the peripheral compartment of the
body.23 The extravascular compartment is the bone marrow
where cells are produced and stored.24,25 The central compart-
ment lives in constant fluctuation between latency and produc-
tion according to external stimuli and feedback regulation;
however, under normal conditions, the majority of cells are
quiescent in the resting phase of the cell cycle (G0).1,7,20 Vas-
cular circulation, also known as the peripheral compartment,
constitutes the second compartment. This is typically where
most mature differentiated cells progress through their life
cycle until they are utilized or undergo apoptosis, at which
point they will be degraded and removed.5 It should be noted
that there is a small percentage (~1%) of stem cells in circulation
at all times and that number can change based on detected sti-
muli, such as the administration of chemotherapy or treatment
with colony-stimulating growth factors during mobilization for
harvest and hematopoietic stem cell transplantation.26
Previous reports describe many different cell lineage
schemes all affirming a uniform concept that an immature
uncommitted cell has unrestricted potential to replicate or can
transform into a mature committed cell.1,6,7,9,21,22,27 Cells are
generally classified into 3 categories and include stem cells,
progenitor cells, and mature differentiated cells.22 All stem
cells appear morphologically similar but are a heterogenous
population and functionally unique.7,28 A relatively small pop-
ulation of stem cells is capable of sufficiently managing the
production needs of the entire hematopoietic system.1,7 They
442
S-Phase Specific
•Anmetabolites
•Topoisomerase I inhibitors
G0 Phase
(Cell at rest)
Figure 1. Phases of a cell cycle including a description of cell division processes and antineoplastic agents active during the corresponding phase.
progress through a life cycle continuum with the youngest cells
having the greatest capacity for self-renewal. Stem cells lose
replicative ability as they age, making them more likely to prog-
ress down a differentiation pathway and into the vasculature over
time.29 When differentiation occurs, a stem cell has capability to
progress through one of multiple lineages present in the bone
marrow as shown in Figure 2.9 Normal adult bone marrow is
regulated by a variety of hormones and cytokines that will influ-
ence the microenvironment and maintain appropriate homeosta-
sis of each different blood cell type circulating in the peripheral
blood.5,24 Pluripotent stem cells are hypothesized to remain
quiescent while the subset of more highly differentiated daughter
cells, or progenitor cells, serve as precursors to traditional cell
lines. Stem cells or progenitor cells receive external stimuli or
interpret changes in the microenvironment and activate to com-
mit to either a myeloid or lymphoid cell line.22 Finally, colony-
forming units and burst-forming units develop into the common
categories of erythroid, granulocyte–monocyte, lymphocyte, and
megakaryocytes. One is defined as the colony-forming unit
spleen (CFU-S), the second is the colony-forming unit granulo-
cyte, erythrocyte, macrophage, and megakaryocyte (CFU-
GEMM) which is responsible for the myeloid stem cell, and the
third is the colony-forming unit lymphocyte (CFU-L) as the
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Journal of Pharmacy Practice 27(5)
Etoposide
Bleomycin
Cell Cycle Nonspecific Agents
M-Phase Specific •Alkylang agents
•Vinca alkaloids •Anthracyclines
•Taxanes •Antumor anbiocs
•Nitrosoureas
•Planum agents
•Steroids
•Asparaginase
•Dacarbazine
lymphoid stem cell.7 An intricate and complex balance is main-
tained under normal conditions with the number of each type of
circulating blood cell and their total body mass remaining
constant.7
Antineoplastic Agents
Antineoplastic agent-associated myelotoxicity is the disruption
of the previously described elements of a functional hemato-
poietic system caused by the administration of antineoplastic
medications. Because traditional cancer drugs display an indis-
criminate toxicity to healthy and cancerous cells alike, under-
standing antineoplastic agent-associated myelosuppression
involves the application of several principles to normal
steady-state proliferation as well as the systematic response
to the detection of any alterations in homeostasis.30
Antineoplastic agents can have an indirect or a direct effect on
the cells of the body. The indirect effect is the action taken by the
drug on the bone marrow microenvironment or hematopoietic
regulators.31 A well-studied indirect effect is anemia that mani-
fests because cis-platinum inhibits the renal release of erythro-
poietin.31 The direct effect, also known as the mechanism of
action, is an interaction between the drug and the cells or their
Barreto et al
Figure 2. Differentiation pathway progression of cellular lineages from pluripotent stem cell to mature blood cell.9
progenitors. An example of a direct effect would be irinotecan sta-
bilizing the topoisomerase I–DNA complex to increase torsional
strain resulting in DNA single- and double-strand breaks during
synthesis. Apoptosis of both tumor and healthy cells occurs as a
result of double-stranded DNA breakage and interference with
the replication process.32
Myelosuppressive Effects of Antineoplastic Agents
Neutropenia is a decrease in white blood cell (WBC) count.
The WBC nadir is the lowest value that neutrophils will decline
to during a cycle of chemotherapy. Nadirs may occur following
antineoplastic agents alone or in combination around 10 to
14 days after administration with complete recovery by day
21 to 28. Other antineoplastic agents, particularly those that are
cell cycle nonspecific like busulfan, nitrosoureas, and mitomy-
cin C, can induce a prolonged duration of neutropenia. Leuko-
cytes, particularly neutrophils, are the first and primary line of
defense against infections, and febrile neutropenia is one of the
most serious consequences of antineoplastic agent administra-
tion. Magnitude of neutropenia depends on the intensity of the
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443
antineoplastic agent regimen and sequential order of drug
administration.33 Risks of febrile neutropenia vary according
to type of cancer and antineoplastic agent regimen.34
Anemia is defined as a decrease in hemoglobin (or hemato-
crit) level from an individual’s baseline value.35 Antineoplastic
agents causing a decrease in red blood cell production lead to
fatigue and decreased activities of daily living. Anemia may
also be an indirect effect of particular cytotoxic agents that
cause a decreased production of erythropoietin by the kidney.
The management of anemia includes packed red blood cell
transfusions or administration of erythropoietin-stimulating
agents. Medications with anemia as a common dose-limiting
toxicity include platinum-containing agents and docetaxel.36,37
Thrombocytopenia is a decrease in platelet production due
to administration of antineoplastic agent potentially requiring
subsequent dosage reductions or therapy delays and incr-
easing the risk of life-threatening spontaneous hemorrhage.
Prevention and management of chemotherapy-induced throm-
bocytopenia remains an unmet clinical need with platelet
transfusions as the mainstay of therapy and thrombopoietin
receptor agonists as an option currently under investigation.38
444
Agents with a dose-limiting toxicity of thrombocytopenia
include carboplatin and gemcitabine, among others.
Impact of Route of Administration on Myelosuppressive
Effects
Efficacy and safety of antineoplastic agents, like most drugs, is
based on the amount administered. In vitro and animal studies
provide models for the expected response to gradually esca-
lated doses of chemotherapy; however, clinical application in
human study is the only method of accurate toxicity assess-
ment.39 Phase I clinical trials are utilized to find the maximum
tolerated dose that demonstrates efficacy and has a manageable
side effect profile. Methotrexate (MTX) is an example where a
drug administered in different doses for different indications
produces variable incidence of toxicity, particularly myelotoxi-
city. Lower doses of MTX, administered for treatment of rheu-
matoid arthritis, have demonstrated relatively infrequent
occurrences of hematologic toxicity, especially when com-
pared to high-dose MTX therapy that is recommended during
treatment of primary central nervous system lymphoma which
necessitates aggressive supportive management and close mon-
itoring of MTX serum concentrations to abrogate complica-
tions associated with high-dose treatment.40-44 Methotrexate
depletes all cells of critical reduced folates necessary for de
novo synthesis of DNA. High-dose MTX requires rescue ther-
apy with folinic acid, a reduced folate commonly known as leu-
covorin, to restore normal DNA replication function and
prevent life-threatening cytopenias. Unfortunately, this return
of DNA replication activity is not isolated to healthy cells but
extends to malignant cells as well. Subtherapeutic doses for
malignancy can result in minimal effects seen in both the body
and the tumor. Actively dividing cells will be affected most by
the antineoplastic agent; however, the disruption may not reach
the critical threshold to induce apoptosis, and the cells will con-
tinue to survive and undergo normal operations. Alternatively,
compensatory mechanisms may increase production to balance
the destruction of cells and maintain adequate distribution that
ultimately neutralizes the effect of the antineoplastic agent.
Perhaps the most concerning is the possibility that the cell will
develop chemoresistance mechanisms including efflux pumps
and activation of antiapoptotic genes.15,45
Method of administration is an important consideration for
the association of antineoplastic agents and the likelihood of
myelotoxicity. Altering the rate of antineoplastic agent admin-
istration can change maximum concentrations achieved and
duration of exposure which may impact overall efficacy and
be associated with different incidences of drug-related toxi-
city.46,47 Bolus administration, the receipt of an agent over a
brief duration, will produce very high concentrations and
affects all cells undergoing active cell division at that time.
Continuous infusion (CIV) of an antineoplastic agent removes
the degree of drug concentration variability experienced with
intermittent dosing and allows maintenance of a fixed drug
concentration achieving increased total drug exposure over
extended periods of time. Additionally, CIV increases the
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Journal of Pharmacy Practice 27(5)
probability that the agent will act on cells that are currently in
active cell division as well as those cells that are activated in
response to stimuli received due to cell disintegration.47 CIV
or oral dosing has been proposed as a mechanism for overcom-
ing chemoresistance.48 Fluorouracil (5-FU) for treatment of col-
orectal cancer is one agent with long-standing debate over the
optimum rate of administration. It has been suggested that work-
ing mechanism of 5-FU changes depending whether the drug is
administered as a bolus or a continuous infusion.49 Studies have
demonstrated superior efficacy when utilizing the prolonged or
continuous intravenous infusion compared to intravenous
bolus.50,51 In addition to improved efficacy, continuous infusion
5-FU compared to bolus 5-FU was associated with a decreased
rate of hematologic toxicity, 4% versus 31%, respectively.52
Dose density is another aspect of drug consideration regarding
chemotherapy-induced myelosuppression. An antineoplastic
agent is administered intermittently between periods of rest
allowing bone marrow to recover. Administration with set time
intervals between treatments that is too brief would increase
the potential for greater hematopoietic toxicity.53 For example,
the combination of carboplatin and paclitaxel in the treatment
of ovarian cancer has been evaluated in many different treatment
schemas. Carboplatin functions as a non–cell cycle-specific
agent, while paclitaxel works during the M-phase to prevent
microtubule formation. While maintaining carboplatin on an
every 3-week schedule, adjustment of paclitaxel from 180 mg/
m2 every 3 weeks to 80 mg/m2 weekly has improved long-
term progression-free and overall survival. Predictably, the
increased targeting of the M-phase led to significantly more ane-
mia in the dose-dense paclitaxel group.54
Multiagent antineoplastic regimens capitalize on diverse
mechanisms of action to maximize efficacy but unfortunately
place patients at an increased risk of myelotoxicity. Variability
in cell cycle specificity plays an important role in the sensitiv-
ity of malignant cells to antineoplastic agents. Antineoplastic
agents can be divided into 2 general classes based on specificity
of cytotoxic effects during the cell cycle.18,55 Cell cycle non-
specific agents are active against proliferating cells regardless
of phase. Conversely, cell cycle phase-specific agents exert
cytotoxic effects primarily during particular cell phases, often
to varying degrees. Overall, knowledge of the cell cycle stages
may assist in designing rational chemotherapeutic combina-
tions while minimizing overlapping toxicity. Long-term hema-
tologic complications can develop when chemotherapy is
administered repeatedly.56-58 Repeated exposure to cytotoxic
therapy over time will insult the bone marrow to a point that
is beyond recovery to previous functionality.59 This permanent
impairment leads to a chronic hypoplastic state associated with
persistent pancytopenia.58 The result will be a toxicity that is
beyond compensation resulting in either survival with com-
plete bone marrow failure or mortality.60
Future Directions
Our understanding of both normal and malignant cells will
continue to develop as efforts are made to optimize the
Barreto et al
treatment of hematologic malignancies. New imaging tech-
niques will allow bone marrow architecture to be assessed, the
bone marrow niche to be analyzed, and cell distributions to be
better quantified.24 More advanced assays are needed to quan-
tify important markers that give information providing a com-
prehensive picture of cell progenitors, current bone marrow
reserve supply, and its overall proliferative capacity.61 Predic-
tion models allowing health care practitioners to better assess a
patient’s susceptibility to antineoplastic agent-induced myelo-
toxicity will enable individualized therapy, as the occurrence of
dose-limiting cytotoxic effects is currently thought to be unpre-
dictable. Finally, the utilization of molecular and genetic infor-
mation coupled with novel targeted therapies that do not
cause antineoplastic agent-induced myelotoxicity will mitigate
the lethal risks associated with antineoplastic agent-induced
myelotoxicity.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
References
1. Smith C. Hematopoietic stem cells and hematopoiesis. Cancer
Control. 2003;10(1):9-16.
2. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for eva-
luation and management. Oncologist. 1999;4(1):1-10.
3. Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationships
between circulating leukocytes and infection in patients with
acute leukemia. Ann Intern Med. 1966;64(2):328-340.
4. Elting LS, Rubenstein EB, Martin CG, et al. Incidence, cost, and
outcomes of bleeding and chemotherapy dose modification
among solid tumor patients with chemotherapy-induced thrombo-
cytopenia. J Clin Oncol. 2001;19(4):1137-1146.
5. Fliedner TM, Graessle D, Paulsen C, Reimers K. Structure and
function of bone marrow hemopoiesis: mechanisms of response
to ionizing radiation exposure. Cancer Biother Radiopharm.
2002;17(4):405-426.
6. Gulati GL, Ashton JK, Hyun BH. Structure and function of the
bone marrow and hematopoiesis. Hematol Oncol Clin North
Am. 1988;2(4):495-511.
7. Hays K. Physiology of normal bone marrow. Semin Oncol Nurs.
1990;6(1):3-8.
8. Lohrmann HP, Schreml W. Cytotoxic drugs and the granulopoie-
tic system. Recent Results Cancer Res. 1982;81:1-222.
9. Travlos GS. Normal structure, function, and histology of the bone
marrow. Toxicol Pathol. 2006;34(5):548-565.
10. Bain BJ, Clark DM, Wilkins B. Bone marrow pathology. 4th ed.
Chichester, UK; Hoboken, NJ: Wiley-Blackwell; 2010.
11. Flemming W. Zellsubstanz, Kern und Zelltheilung. Leipzig: F.C.
W. Vogel; 1882.
12. Hill BT, Baserga R. The cell cycle and its significance for cancer
treatment. Cancer Treat Rev. 1975;2(3):159-175.
Downloaded from jpp.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 26, 2014
445
13. Chabner BA, Roberts TG Jr. Timeline: chemotherapy and the war
on cancer. Nat Rev Cancer. 2005;5(1):65-72.
14. Ivanchuk SM, Rutka JT. The cell cycle: accelerators, brakes, and
checkpoints. Neurosurgery. 2004;54(3):692-699.
15. Shah MA, Schwartz GK. Cell cycle-mediated drug resistance: an
emerging concept in cancer therapy. Clin Cancer Res. 2001;7(8):
2168-2181.
16. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle:
a review of regulation, deregulation and therapeutic targets in
cancer. Cell Prolif. 2003;36(3):131-149.
17. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the
order of cell cycle events. Science. 1989;246(4930):629-634.
18. Vietti TJ, Valeriote FA. Conceptual basis for use of chemothera-
peutic agents and their pharmacology. Pediatr Clin North Am.
1976;23(1):67-92.
19. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in
cancer. Nature. 2001;411(6835):342-348.
20. Fliedner TM. The role of blood stem cells in hematopoietic cell
renewal. Stem Cells. 1998;16(6):361-374.
21. Tannock IF. Experimental chemotherapy and concepts related to
the cell cycle. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;
49(2):335-355.
22. Parchment RE, Gordon M, Grieshaber CK, et al. Predicting hema-
tological toxicity (myelosuppression) of cytotoxic drug therapy
from in vitro tests. Ann Oncol. 1998;9(4):357-364.
23. Risitano AM, Maciejewski JP, Selleri C, et al. Function and mal-
function of hematopoietic stem cells in primary bone marrow fail-
ure syndromes. Curr Stem Cell Res Ther. 2007;2(1):39-52.
24. Shen Y, Nilsson SK. Bone, microenvironment and hematopoiesis.
Curr Opin Hematol. 2012;19(4):250-255.
25. Walkley CR. Erythropoiesis, anemia and the bone marrow micro-
environment. Int J Hematol. 2011;93(1):10-13.
26. Gordon MY. Physiology and function of the haemopoietic micro-
environment. Br J Haematol. 1994;86(2):241-243.
27. Botnick LE, Hannon EC, Hellman S. Nature of the hemopoietic
stem cell compartment and its proliferative potential. Blood Cells.
1979;5(2):195-210.
28. Hellman S, Reincke U, Botnick L, et al. Functional organization
of the hematopoietic stem cell compartment: implications for can-
cer and its therapy. J Clin Oncol. 1983;1(4):277-284.
29. Snoeck HW. Aging of the hematopoietic system. Curr Opin
Hematol. 2013;20(4):355-361.
30. Kane B. Cancer chemotherapy: teaching old drugs new tricks.
Ann Intern Med. 2001;135(12):1107-1110.
31. Gale RP. Antineoplastic chemotherapy myelosuppression:
mechanisms and new approaches. Exp Hematol. 1985;13(suppl
16):3-7.
32. Verschraegen CF, Natelson EA, Giovanella BC, et al. A phase I
clinical and pharmacological study of oral 9-nitrocamptothecin,
a novel water-insoluble topoisomerase I inhibitor. Anticancer
Drugs. 1998;9(1):36-44.
33. Dale DC. Colony-stimulating factors for the management of neu-
tropenia in cancer patients. Drugs. 2002;62(suppl 1):1-15.
34. Bennett CL, Djulbegovic B, Norris LB, et al. Colony-stimulating
factors for febrile neutropenia during cancer therapy. N Engl J
Med. 2013;368(12):1131-1139.
446
35. Tefferi A. Anemia in adults: a contemporary approach to diagno-
sis. Mayo Clin Proc. 2003;78(10):1274-1280.
36. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults:
incidence and treatment. J Natl Cancer Inst. 1999;91(19):
1616-1634.
37. Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Can-
cer Anaemia survey (ECAS): a large, multinational, prospective
survey defining the prevalence, incidence, and treatment of anae-
mia in cancer patients. Eur J Cancer. 2004;40(15):2293-2306.
38. Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for
management of chemotherapy-induced thrombocytopenia. Sup-
port Care Cancer. 2014;22(5):1217-1222.
39. Connors T. Anticancer drug development: the way forward.
Oncologist. 1996;1(3):180-181.
40. Gilani ST, Khan DA, Khan FA, et al. Adverse effects of low dose
methotrexate in rheumatoid arthritis patients. J Coll Physicians
Surg Pak. 2012;22(2):101-104.
41. Gutierrez-Urena S, Molina JF, Garcia CO, et al. Pancytopenia
secondary to methotrexate therapy in rheumatoid arthritis. Arthri-
tis Rheum. 1996;39(2):272-276.
42. Batchelor T, Carson K, O’Neill A, et al. Treatment of primary
CNS lymphoma with methotrexate and deferred radiotherapy: a
report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-1049.
43. Rubenstein JL, Gupta NK, Mannis GN, et al. How I treat CNS
lymphomas. Blood. 2013;122(14):2318-2330.
44. Skarin AT, Zuckerman KS, Pitman SW, et al. High-dose metho-
trexate with folinic acid in the treatment of advanced non-
Hodgkin lymphoma including CNS involvement. Blood. 1977;
50(6):1039-1047.
45. Giai M, Biglia N, Sismondi P. Chemoresistance in breast tumors.
Eur J Gynaecol Oncol. 1991;12(5):359-373.
46. Aschele C, Sobrero A, Faderan MA, et al. Novel mechanism(s) of
resistance to 5-fluorouracil in human colon cancer (HCT-8) sub-
lines following exposure to two different clinically relevant dose
schedules. Cancer Res. 1992;52(7):1855-1864.
47. Vogelzang NJ. Continuous infusion chemotherapy: a critical
review. J Clin Oncol. 1984;2(11):1289-1304.
48. Gardner SN. Cell cycle phase-specific chemotherapy: computa-
tional methods for guiding treatment. Cell Cycle. 2002;1(6):
369-374.
Downloaded from jpp.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 26, 2014
Journal of Pharmacy Practice 27(5)
49. Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal
cancer–a tale of two drugs: implications for biochemical modula-
tion. J Clin Oncol. 1997;15(1):368-381.
50. Efficacy of intravenous continuous infusion of fluorouracil com-
pared with bolus administration in advanced colorectal cancer.
Meta-analysis Group In Cancer. J Clin Oncol. 1998;16(1):
301-308.
51. Seifert P, Baker LH, Reed ML, et al. Comparison of continuously
infused 5-fluorouracil with bolus injection in treatment of patients
with colorectal adenocarcinoma. Cancer. 1975;36(1):123-128.
52. . Toxicity of fluorouracil in patients with advanced colorectal can-
cer: effect of administration schedule and prognostic factors.
Meta-analysis group in cancer. J Clin Oncol. 1998;16(11):
3537-3541.
53. DeWys WD, Goldin A, Man, El N. Hematopoietic recovery after
large doses of cyclophosphamide: correlation of proliferative
state with sensitivity. Cancer Res. 1970;30(6):1692-1697.
54. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense pacli-
taxel once a week in combination with carboplatin every 3 weeks
for advanced ovarian cancer: a phase 3, open-label, randomised
controlled trial. Lancet. 2009;374(9698):1331-1338.
55. Bhuyan BK, Scheidt LG, Fraser TJ. Cell cycle phase specificity of
antitumor agents. Cancer Res. 1972;32(2):398-407.
56. Minderman H, Linssen P, van der Lely N, et al. Toxicity of idar-
ubicin and doxorubicin towards normal and leukemic human bone
marrow progenitors in relation to their proliferative state. Leuke-
mia. 1994;8(3):382-387.
57. Bergsagel DE, Robertson GL, Hasselback R. Effect of cyclopho-
sphamide on advanced lung cancer and the hematological toxicity
of large, intermittent intravenous doses. Can Med Assoc J. 1968;
98(11):532-538.
58. Schein PS, Winokur SH. Immunosuppressive and cytotoxic che-
motherapy: long-term complications. Ann Intern Med. 1975;
82(1):84-95.
59. Trainor KJ, Seshadri RS, Morley AA. Residual marrow injury fol-
lowing cytotoxic drugs. Leuk Res. 1979;3(4):205-210.
60. Lohrmann HP. The problem of permanent bone marrow damage
after cytotoxic drug treatment. Oncology. 1984;41(3):180-184.
61. Dale DC. Understanding neutropenia. Curr Opin Hematol. 2014;
21(1):1-2.