Hall Book Ch 27 (Chemo Agents from the Perspective of the Radiation Biologist) Flashcards
( ) chemotherapeutic agents have been used successfully to cure a few rapidly proliferating tumors.
Combinations of drugs are used routinely for the treatment of various malignancies.
Most anticancer drugs work by affecting ( ).
Single, DNA synthesis or function
Inevitably, many traditional anticancer drugs are toxic to stem cells of the intestinal epithelium and hematopoietic stem cells because they have a ( ).
Some of the new targeted therapy drugs (e.g., cetuximab) have the potential to increase ( ) on normal tissue toxicity.
high growth fraction, tumor response with minimal effect
Agents that are mainly effective during a particular phase of the cell cycle, such as the S phase or M phase, are said to be cell ( ).
Agents whose action is independent of the position of the cell in the cycle are said to be cell cycle nonspecific, or phase nonspecific.
cycle specific, or phase specific
Many classically used chemotherapeutic agents fall into one of several classes: Alkylating agents, which are highly active, with the ability to substitute alkyl groups for hydrogen atoms in DNA, include ( ).
nitrogen mustard derivatives, cyclophosphamide, chlorambucil, melphalan, and the nitrosoureas (BCNU and CCNU)
Antibiotics, which bind to DNA and inhibit DNA and RNA synthesis, include dactinomycin, doxorubicin, daunorubicin, and bleomycin.
Antimetabolites, which are analogues of the normal metabolites required for
cell function and replication, include methotrexate, 5-FU, cytarabine, and 5-
azacytidine.
Many of the newer and widely used drugs do not fall into any of these classes,
including the vinca alkaloids, the taxanes, procarbazine, hydroxyurea,
platinum complexes, topoisomerase inhibitors, and “targeted therapy” agents
that target a specific pathway that may be elevated in some tumors
(cetuximab [Erbitux], trastuzumab [Herceptin], imatinib mesylate [Gleevec],
and rituximab [Rituxan]).
Dose–response relationships for many chemotherapeutic agents resemble those
for radiation, with drug concentration replacing absorbed dose; that is, there
is an initial shoulder followed by an exponential relationship between
surviving fraction and dose. The exceptions are doxorubicin, bleomycin,
dactinomycin, and taxanes, which have dose–response curves that are
concave upward.
At best, traditional anticancer drugs kill cells by first-order kinetics; that is, a
given dose kills a constant fraction of cells. Consequently, the chance of
eradicating a cancer is greatest if the population size is small (i.e., there is an
inverse relationship between curability and tumor cell burden) at the
initiation of chemotherapy.
Studies of sublethal damage and potentially lethal damage are more confusing
and less clear-cut for drugs than for radiation.
Some drugs (e.g., bleomycin) are more toxic to aerated than to hypoxic cells.
For these drugs, free radicals are involved in the mechanism of cell killing, as
is the case for x-rays.
Some drugs (such as mitomycin C) are more toxic to hypoxic than to aerated
cells because they undergo bioreduction.
This applies also to tirapazamine, as
discussed in Chapter 26.
Other drugs (including 5-FU, methotrexate, cis-platinum, and the nitrosoureas)
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appear to be equally cytotoxic to aerated and hypoxic cells.
The effectiveness of chemotherapeutic agents decreases with distance from a
capillary because the drug concentration falls off because of metabolism and
because cells are not proliferating because they are hypoxic.
Drug resistance is the biggest single problem in chemotherapy. For example,
cells exposed continuously to low levels of doxorubicin become very
resistant to subsequent treatments with this drug.
The usual strategy to overcome resistance to cytotoxic chemotherapy is to use
a battery of drugs that produce cytotoxicity by diverse mechanisms.
The strategy to overcome resistance to targeted therapy is to identify the
molecular basis of resistance.
Pleiotropic resistance occurs if the development of resistance to one drug
results in cross-resistance to other drugs with a different mechanism of
action.
Resistance may be associated with the following: decreased drug accumulation
and the expression of p-glycoproteins in the cell membrane from gene
amplification, elevated levels of glutathione, and marked increase in DNA
repair.
Radioresistance and chemoresistance may occur together, but radiation rarely
induces chemoresistance and vice versa.
The adjunct use of chemotherapy with radiation may involve sequential or
concurrent treatments.
The extent to which chemotherapeutic agents show synergy with radiation
varies widely. Some interact strongly (e.g., doxorubicin, gemcitabine), others
less so, and some not at all (see Table 27.1.)
Antiangiogenic agents can enhance the efficacy of fractionated radiotherapy
but can increase normal tissue toxicity when combined with SBRT.
Some agents penetrate the blood–brain barrier (e.g., BCNU, temozolomide,
cytosine arabinoside, hydroxyurea), others only at high intravenous doses
(e.g., methotrexate), whereas many do not cross the blood–brain barrier at all
(see Table 27.1).
A therapeutic gain requires a differential between tumor and normal tissue.
This may be achieved by exploiting one or more of the following tumor
characteristics: genetic instability, rapid proliferation, cell age distribution,
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hypoxia, pH, and dysregulated signaling pathways (e.g., EGFR).
Sensitive cells can be killed only once. Tumor heterogeneity should be
exploited by using a combination of drugs effective against different cell
subpopulations.
Sensitivity of individual tumors to chemotherapeutic agents with or without
radiation may be assessed by the following: in vitro clonogenic assays,
xenografts in nude mice, micronuclei in treated cells.
Synthetic lethality is the basis for using PARP inhibitors to treat patients with
defects in the homologous recombination repair (HRR) such as BRCA1.
Targeted therapies such as cetuximab have been demonstrated to work well in
combination with radiotherapy in the treatment of head and neck cancer.
PD-1 is located on the surface of a T cell, and if it binds to PD-L1 or PD-L2,
the T cell becomes inactive.
T-cell checkpoint therapeutics work by blocking inhibitory signals (PD-L1 or
PD-L2 binding to PD-1) that prevent activated T-cells from attacking the
cancer.
T-cell checkpoint therapeutics are now being tested in combination with
radiotherapy and in some cases have resulted in dramatic responses.
