Page 205 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

184 PART 3 Therapeutic Modalities for the Cancer Patient

TABLE 12.1 Measures of Response in Cancer Therapy and Treatment
Response Term Abbreviation Description
VetBooks.ir Complete remission/response CR Complete disappearance of tumor(s) and symptoms of disease.

Decrease in tumor volume of ≥50% or decrease in tumor maximum diam-
PR
Partial remission/response
eter of >30%.
Stable disease SD Neither an increase nor a decrease in tumor size (e.g., <30% reduction or
<20% increase in tumor maximum diameter).
Progressive disease PD Increase in tumor volume of >25% or increase of tumor maximum diameter
of >20%; appearance of new lesions.
Median response duration/median survival time MRD/MST The median value for a group of individuals treated with a given therapy in
terms of the length of time they achieved a complete or partial remission
(MRD) or length of survival after implementation of therapy (MST).
Progression-free interval/progression-free survival PFI/PFS The amount of time elapsed without evidence of progressive tumor growth
(PFI) or survival without progressive growth of the tumor from treatment
start (PFS).
Disease-free interval/disease-free survival DFI/DFS The amount of time that elapses without disease recurrence (DFI) or survival
(DFS) of the patient after therapy.

with a given histotype. Human cancer cell line databases that
include both genomic and drug response data are publicly avail- Drug
able and include the NCI60 (https://dtp.cancer.gov), Cancer Apoptosis
Cell Line Encyclopedia (CCLE) (https://portals.broadinstitute. Damage
org/ccle), and Genomics of Drug Sensitivity in Cancer (CCSG) signals Uptake
(https://www.cancerrxgene.org). The rich gene expression and
other features of these cell lines allow for drug sensitivity and DNA Drug
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genotypic characteristics to be explored. The use of canine tumor repair
cell line panels to screen drug sensitivity is becoming established DNA Target Non-DNA
targets
as a viable way to identify potential drug combinations for further damage
testing as well. 4
Chemosensitivity depends on a number of factors, including Block DNA
drug uptake into the cell, interaction with a cellular target, genera- synthesis
tion of lethal damage to important cellular macromolecules, repair
of potentially lethal damage, and the cell’s response to generated • Fig. 12.2 Processes involved in the pharmacologic activity and associ-
damage as depicted in Fig. 12.2. Uptake of some cancer chemo- ated chemosensitivity of chemotherapeutic agents in tumor cells. Associ-
therapeutic agents occurs via passive diffusion because of their ated processes include drug uptake, interaction with drug target, effect
lipid-soluble properties, whereas other compounds are actively on DNA and associated DNA repair, and the cellular response to these
transported into tumor cells. Melphalan is actively transported effects.
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into cells by two amino acid transporters, and blocking transport
with amino acid substrates or analogs can significantly affect cyto- determines cellular fate. The generation of cellular damage is a
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toxicity. Other examples include nucleoside transporters used by consequence of interaction with a cellular target and can be either
7
Ara-C and gemcitabine and the reduced folate carrier system a primary or a secondary event. In general, for DNA-damaging
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involved in methotrexate uptake. The intracellular target(s) for agents, the resulting DNA lesions are a result of the interplay of
specific chemotherapeutic agents can play a role in determining DNA binding and DNA repair. For example, DNA strand breaks
sensitivity based on their levels and the nature of the interaction. that result from O -methyl guanine lesions are because of aberrant
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For example, topoisomerase IIα levels can play a role in the sen- mismatch repair processes and subsequent replication. DNA
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sitivity of tumor cells to doxorubicin (DOX), 10,11 as altered levels damage also triggers response pathways that can result in cell cycle
via decreased gene copy or transcriptional downregulation leads arrest to allow for repair and subsequent survival, or the triggering
to a decrease in sensitivity (resistance). The opposite is true for of apoptotic machinery that ultimately results in cell death. The
thymidylate synthetase levels and 5-fluorouracil (5-FU) toxicity, definition of cellular response, be it mitotic catastrophe, apopto-
where increased levels of enzyme correlate with a decrease in sen- sis, necrosis, autophagy, or cellular stasis, is dependent on an intri-
sitivity to 5-FU. Although the nature of the interaction with the cate interplay of survival and death signaling and is often specific
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target is different for DOX and 5-FU, the fact that altered target to the agent, the dose at the critical target, and the cell lineage.
levels can modulate response show how quantitative interactions Alterations in pro- and antiapoptotic signaling clearly play a role
with the target can alter drug sensitivity. in tumorigenesis and response to therapy, and the effect of anti-
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The extent of cellular damage, potential repair of that damage, apoptotic signaling in lymphoma by the mediators bcl-2 and sur-
and the cellular response occur in a tightly knit continuum that vivin seem the most clear both in regard to chemosensitivity 16–18