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318 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 319

DRUG RESISTANCE is clear that many tissues, including marrow, contain stem cells capable
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Inadequate treatment of a sensitive tumor tends to select for the out- of repopulating organs, even from single cells. Likewise, many tumors
growth of drug-resistant clones of the original tumor. The reasons for contain stem cells, which, on careful evaluation, preserve many of the
emergence of drug resistance are manifold. Cancer cells often harbor surface antigens of their normal counterpart, and display resistance to
basic defects in DNA repair as one of their hallmark mutations and DNA damage, reactive oxygen species generated by drugs or irradia-
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spontaneously generate drug-resistant mutants, even in the absence of tion, and readily export toxic natural products. It is possible, but still
drug exposure. Thus it has been demonstrated in the specific example to be established, that these drug-resistant stem cells represent the ulti-
of imatinib treatment of CML that drug-resistant cells, carrying spe- mate barrier to successful cancer treatment.
cific mutations in the BCR-ABL gene, can be identified in marrow prior
to treatment and become the dominant tumor population under the
selective pressure of drug treatment. A similar finding of pretreatment CELL-CYCLE-SPECIFIC AGENTS
5
mutations explains drug resistance to inhibitors to the epidermal growth A number of anticancer drugs, particularly those developed during the
factor receptor in non–small-cell lung cancer. In addition, many cancer era of cytotoxic chemotherapy, exert their antitumor effects on DNA syn-
9
drugs, especially alkylating agents, and irradiation are mutagenic and thesis. Cells are thus most vulnerable during periods of active DNA syn-
increase the rate of generation of drug-resistant mutants, as demon- thesis (S-phase), and least affected during quiescent (G ) stages of their
0
strated in the selection of mismatch repair mutants by temozolomide. life cycle. Thus tumors that have a high proliferative rate, such as leuke-
10
To discourage the outgrowth of resistant cells, multiple agents with dif- mias and aggressive lymphomas, are most vulnerable to these agents.
fering mechanisms of resistance should be used simultaneously, because
the likelihood of there being a doubly or triply resistant cell is the prod-
uct of the probabilities of the independent drug-resistant mutations METHOTREXATE
occurring at the same time in a single cell. The probability of a cell divi- Farber and associates showed that the folate antagonist aminopterin
sion resulting in mutation at any given genetic locus is approximately induced a complete remission in children with ALL, thereby launch-
10 for any given episode of cell division in somatic cells; thus the prob- ing the modern era of chemotherapy. Unfortunately, these remissions
–6
ability of two independent mutations arising in the same cell is 10 . were short-lived, and the leukemia invariably became resistant to fur-
–12
Mutation rates may be distinctly higher in tumor cells and may be fur- ther treatment. Subsequently, methotrexate, a 4-amino, N-10 methyl
ther increased by exposure to alkylating agents and irradiation. Some analogue of folic acid, supplanted aminopterin because it had more
mutations, such as those affecting apoptosis, may confer resistance to predictable side effects. Methotrexate continues to be a key drug in the
multiple agents of diverse mechanisms of action. Thus, the probability induction and maintenance therapy of ALL, in the intrathecal prophy-
of encountering MDR cells is much higher in reality. laxis and treatment of CNS leukemia, in the primary treatment of CNS
In choosing drugs for combination therapy, one must bear in lymphomas, and in combination therapy of high-grade lymphomas.
mind potential mechanisms of resistance. Classical MDR occurs as a
consequence of increased expression of drug efflux pumps such as the Mechanisms of Action
P-glycoprotein or the MDR-associated proteins (MRPs), 11,12 and confers Methotrexate enters cells through an active uptake process mediated
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resistance to a broad spectrum of agents derived from natural products, in most tumor cells by the reduced folate transporter and is actively
including taxanes, anthracyclines, vinca alkaloids, and epipodophyl- effluxed from cells by the MRP class of exporters. A second uptake
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lotoxins, and potentially to a number of “targeted” agents. Other mech- transporter, the membrane folate-binding protein (FBP), has lower
anisms of resistance that induce amplification of a target gene, such as affinity for methotrexate, but may contribute to uptake of other anti-
dihydrofolate reductase (DHFR) or BCR-ABL kinase, may be highly folates, such as pemetrexed. The FBP is found on many solid malignan-
14
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specific for a single drug. Table 22–2 lists the common mechanisms cies, and is an active target for folate analogue- and antibody-mediated
of resistance. Although the presence of these biochemical changes drug development. A third, low pH transporter may also participate in
is not routinely determined in tumor biopsies prior to therapy, these methotrexate influx, particularly in the intestine, but its role in tumor
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mechanisms should be considered in developing new protocols and in uptake is uncertain. By virtue of its 4-amino substitution, methotrex-
choosing cytotoxic therapy. In relapse after targeted therapy of CML or ate potently inhibits the enzyme DHFR, which recycles oxidized dihy-
certain non–small cell lung cancers, the choice of second-line therapies drofolate to its active tetrahydrofolate state. Inhibition of DHFR leads to
may rely on studies of tumor cell resistance, as reflected in repeat biop- rapid depletion of the intracellular tetrahydrofolate coenzymes required
sies of solid tumors or cell sampling in CML. for thymidylate and purine biosynthesis. As a result, DNA synthesis is
In addition to drug-specific mechanisms of resistance, mutations blocked and cell replication stops. Methotrexate is retained intracellu-
that abolish recognition of DNA damage, such as the loss of compo- larly as a consequence of an enzymatic process that adds up to six glu-
nents of the mismatch repair gene complex (MLH6 or MSH2) seem tamate moieties in an unusual peptide linkage to the γ-carboxyl group
15
to block initiation of apoptosis by cisplatin, thiopurines, or alkylating of the drug (Fig. 22–1). Polyglutamation is an important determinant of
agents. Other mutations that block the induction of apoptosis, such as leukemic cell sensitivity to methotrexate. Methotrexate polyglutamates,
loss of p53 or overexpression of the antiapoptotic factors such as BCL-2, in addition to their long persistence in cells and their potent inhibition
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may render tumor cells insensitive to a broad array of drugs and modal- of DHFR, have greatly increased inhibitory effects on other folate-de-
ities, including ionizing irradiation, alkylating agents, antimetabolites, pendent enzymes, including thymidylate synthase and enzymes that
and anthracyclines. Although the specific contribution of p53 mutation synthesize purines (Fig. 22–2). Cells that convert the drug to polyglu-
and altered apoptosis to clinical resistance is still uncertain, emerging tamates efficiently, such as leukemic myeloblasts and lymphoblasts,
evidence suggests that these factors are commonly associated with clin- are more susceptible to the drug than are normal myeloid precursors,
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ical resistance and aggressive tumor growth and may be more relevant which have limited capability for polyglutamation. Accumulation of
causes of drug resistance in the clinic than are the classical drug-specific polyglutamates correlates with increased cytotoxicity and treatment
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mechanisms found in experimental tumors. response in childhood lymphoblastic leukemia. Hyperdiploid ALLs
The contribution of tumor stem cells to treatment resistance and are particularly efficient in transporting methotrexate and in producing
disease recurrence is an intriguing, but as yet undefined, possibility. It polyglutamated species, factors that may contribute to their favorable

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