Page 206 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 12 Cancer Chemotherapy 185

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and response to therapy in humans and dogs 19–21 ; however, a clear paclitaxel and topoisomerase I for camptothecin affect binding
understanding of the role of damage response and active cell death of drug and interaction with the target, thus conferring resistance.
Damage repair in cancer cells treated with chemotherapy com-
pathways in chemosensitivity and response in solid tumors is still
VetBooks.ir lacking. monly refers to DNA repair processes, as a majority of chemo-
therapy agents work at the level of the DNA. Resistance conferred
Tumor Cell Resistance
Acquired resistance, or selection of resistant cells, during the through alteration in DNA repair includes not only the induction
of specific processes to repair discrete lesions but also more global
treatment process is thought to be one of the major mechanisms DNA repair processes such as postreplication and mismatch
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of therapeutic failure during cancer drug therapy. Resistance of repair. Multiple studies have shown that enhanced removal of
tumor cells to chemotherapeutic agents can be drug and mecha- platinum adducts from tumor cell DNA correlates with acquired
nism dependent or can occur through a multidrug mechanism. In resistance to cisplatin, 42–44 although the exact mechanism(s) and
general, acquired resistance to a specific agent can develop via a protein(s) responsible for repair of these lesions are unknown. The
variety of mechanisms associated with drug uptake, drug metabo- bulky DNA adducts generated by many cancer chemotherapeutic
lism/detoxification, target modification, damage repair, or damage agents can cause replicative gaps in DNA that require postreplica-
recognition and response. Changes in intracellular drug concen- tion surveillance and repair. The ability of cells to bypass these
trations can come about either because of a decrease in drug bulky lesions and interstrand cross-links during DNA replication
uptake or through increased efflux. Decreased expression of trans- is important in tolerance to agents causing these types of DNA
porters known to play a role in drug uptake has been observed in damage (cisplatin, mitomycin C, melphalan), and multiple DNA
resistance to treatment with melphalan in human breast cancer repair pathways can account for this release from the DNA repli-
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cells, and acquired resistance to methotrexate in KB carcinoma cation block. The fact that DNA repair pathways and processes
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cells. The induction of drug efflux pumps in response to drug are redundant and nondiscrete and that both lesion-specific and
treatment is a primary mechanism for multidrug resistance and global processes seem to play a role in determining drug resistance
will be discussed later in this section. highlights the problems associated with attributing specific resis-
Alterations in metabolic or detoxification pathways within tance phenotypes to specific proteins or pathways. This problem
tumor cells are another mechanism by which acquired resistance may be addressed with unbiased genomic or proteomic approaches
may be acquired. As many chemotherapeutic agents are electro- that profile multiple factors.
philic based on their DNA-binding properties, enhancement of Tumor cell drug resistance associated with alterations in cel-
conjugation reactions with nucleophiles such as glutathione is a lular damage recognition and response is generally associated with
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plausible mechanism of resistance. Induction of glutathione- defects in apoptosis. Generally, these alterations in apoptosis
S-transferases has been shown to be a mechanism by which tumor signaling are not a response to therapy but rather are preexist-
cells can acquire resistance to nitrogen mustards. 25,26 Although ing and play a role in initial sensitivity. This is exemplified in a
tumor cells themselves generally have limited drug metabolism study showing that although survivin expression was shown to be
capabilities, some metabolic pathways can play a role in the resis- predictive for response to CHOP (Cyclophosphamide, Hydroxy-
tance phenotype. For example, the sensitivity of tumor cells to daunorubicin, Oncovin [vincristine], and Prednisone) therapy
5-FU is inversely correlated with the expression of dihydropyrimi- in canine lymphoma, survivin expression in patient-matched
dine dehydrogenase, 27–29 the enzyme predominantly responsible samples pretreatment and at relapse showed no significant differ-
for the metabolism of 5-FU to the inactive 5-FUH metabolite. ence. This suggests that the role of antiapoptotic, prosurvival sig-
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For the prodrug gemcitabine, which must be phosphorylated to naling diminishes the initial response to drug therapy as opposed
the di- and triphosphate forms before eliciting an inhibitory effect to facilitating survival of initially drug-sensitive clones through an
on DNA synthesis, 31,32 the enzyme responsible for this metabolic acquired mechanism.
activation, deoxycytidine kinase, 33,34 is decreased in pancreatic Some mechanisms of acquired resistance result in a phenotype
tumor cells made resistant to this drug. This interplay between in which the tumor is resistant to multiple chemotherapeutic
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metabolic detoxification and activation, predominantly with agents, or multidrug resistant (MDR). Some of the mechanisms
nucleotide analogs, leads to complex scenarios involving upregu- discussed earlier, including DNA repair, enhanced metabolism or
lation of catabolic processes and the downregulation of anabolic detoxification, and resistance to apoptosis can result in resistance
processes influencing the cellular pharmacology of these agents. to multiple agents; however, the “MDR phenotype” generally
Modifications in the cellular target of a given drug usually per- refers to tumor cells expressing individual or multiple members of
tain to mutations in the target protein leading to a decrease in the ATP-binding cassette (ABC) transporter family, which plays a
affinity or absence of drug interaction. These modifications can primary role in active efflux of drugs from cells. Forty-eight ABC
include a decrease in the levels of a specific target responsible for genes have been identified in the human genome, and currently
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the generation of a toxic product, increases in target levels to ame- 15 members of the ABC transporter family have been recognized
liorate the effect of target inhibition, or target mutations such that that include a cancer drug as a substrate for transport. These
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the drug can no longer interact in a manner detrimental to the include the well-studied and well-characterized PGP/MDR1
tumor cell. Decreased topoisomerase II gene expression and activ- (ABCB1), MXR/BCRP (ABCG2), MRP1 (ABCC1), and MRP2
ity has been observed in human lung and colon cells with acquired (ABCC2). The basic function of the ABC transporters is con-
resistance to the epipodophyllotoxins etoposide and teniposide, served across the family and involves the ATP-dependent trans-
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whose antitumor activity involves topoisomerase II–dependent port of xenobiotics and endogenous substrates from the inside
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DNA strand break formation. Target amplification as a mecha- of the cell to the extracellular space. The role of ABC transport-
nism of acquired resistance has been observed in methotrexate ers in multidrug resistance of canine and feline cancers is poorly
resistance, where gene amplification and increased dihydrofo- explored; however, ABCB1 is expressed in canine lymphoma,
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late reductase (DHFR) levels allow for cells to overcome DHFR mammary tumors, and canine and feline primary pulmonary
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inhibition. Mutations in targets such as β-tubulin in the case of carcinomas. ABCC1, ABCC2, ABCC5, ABCC10, and ABCG2
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