DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
G 1
checkpoints
G 1 G 2 G 2
G O
CELL CYCLE NON-SPECIFIC DRUG
alkylating drugs, nitrosoureas,
antitumor antibiotics, procarbazine,
cisplatin, dacarbazine
M
S
S PHASE
SPECIFIC DRUGS
cytosine arabinoside,
hydroxyurea
S PHASE SPECIFIC
SELF-LIMITING
6-mercaptopurine,
methotrexate
M PHASE SPECIFIC DRUGS
vincristine, vinblastine, paclitaxel
Figure 60–2. Cell cycle specificity of antineoplastic agents.
damaging DNA. Their toxicity is greatest during the S,
or DNA synthetic, phase of the cell cycle. Others, such
as the vinca alkaloids and taxanes, block the formation
of a functional mitotic spindle in the M phase. These
agents are most effective on cells entering mitosis, the
most vulnerable phase of the cell cycle. Accordingly,
human neoplasms most susceptible to chemotherapeutic
measures, including leukemias and lymphomas, are
those having a high percentage of proliferating cells.
Normal tissues that proliferate rapidly (bone marrow,
hair follicles, and intestinal epithelium) are thus highly
susceptible to damage from cytotoxic drugs.
Slowly growing tumors with a small growth fraction
(e.g., carcinomas of the colon or non–small cell
lung cancer) are less responsive to cycle-specific drugs.
More effective are agents that inflict high levels of
DNA damage (e.g., alkylating agents) or those that
remain at high concentrations inside the cell for
extended periods of time (e.g., fluoropyrimidines). The
results of comparative clinical trials provide evidence
for the most effective regimens for specific tumors. The
clinical benefit of cytotoxic drugs has primarily been
measured by radiological assessment of drug effects on
tumor size; newer “targeted” agents, however, may simply
slow or halt tumor growth so their effects may best
be measured in the assessment of time to disease progression.
More recently, there is growing interest in
designing drugs that selectively kill the stem cell component
of tumors because these cells are believed to be
responsible for the continuous proliferation and repopulation
of tumors after a toxic exposure to chemotherapy
or targeted therapy. For example, bone marrow and
epithelial tissues contain a compartment of normal nondividing
stem cells that display resistance to cytotoxic
drugs and retain the capacity to regenerate the normal
cell population. Tumor stem cells exhibit the same
resistance to chemotherapy, radiotherapy, and oxidative
insults, and thus they may represent a significant barrier
to the cure of neoplasms (Diehn et al., 2009).
Although cells from different tumors display differences
in the duration of their transit through the cell
cycle, and in the fraction of cells in active proliferation,
all cells display a similar pattern of cell cycle progression
(Figure 60-2):
• a phase that precedes DNA synthesis (G 1
)
• a DNA synthetic phase (S)
• an interval following the termination of DNA synthesis
(G 2
)
• the mitotic phase (M) in which the cell, containing a
double complement of DNA, divides into two daughter
G 1
cells
• a probability of moving into a quiescent state (G 0
)
and failing to move forward for long periods of time
At each transition point in the cell cycle, specific
proteins such as p53 and chk-1 and 2, monitor the
integrity of DNA and, upon detection of DNA damage,
may initiate DNA repair processes or, in the presence of
massive damage, direct cells down a cell death (apoptosis)
pathway. Some cancer chemotherapeutic drugs act
at specific phases, in the cell cycle, mainly at the S phase
and M phase; other agents are cytoxic at any point in the
cell cycle and are termed cell cycle phase nonspecific
agents.
Each transition point in the cell cycle requires the
activation of specific cyclin-dependent kinases (CDKs),
which, in their active forms, couple with corresponding
regulatory proteins called cyclins. The proliferative
impact of CDKs is in turn dampened by inhibitory proteins
such as p16. Tumor cells often exhibit changes in
cell-cycle regulation that lead to relentless proliferation
(e.g., mutations or loss of p16 or other inhibitory components
of the so-called retinoblastoma pathway,
enhanced cyclin or CDK activity). Consequently, CDKs
and their effector proteins have become attractive targets
for discovery of anti-neoplastic agents.
Because of the central importance of DNA to the
identity and functionality of a cell, elaborate mechanisms
(“checkpoints”) have evolved to monitor DNA