Download 1 - Wk 1-2

Pharmacokinetics and principles of action of
Chemotherapeutic drugs
1. Outline the major classes of anti-cancer drugs.
2. Describe, using examples, the mode of action of the major classes of anticancer
drugs: antimetabolites, intercalating agents, antimitotics etc
Antimetabolites:
These function at the level of DNA synthesis, interfering with the metabolism of
compounds necessary for DNA, RNA or protein synthesis (specifically nucleic acid bases
cytosine, thymine, adenine, guanine) & preventing their incorporation into newly formed
DNA material. Two types of drug are available:
1. Chemical modification of a nucleic acid so that the drug rather then the true
nucleic acid is incorporated into the DNA, preventing accurate replication.
E.g. 5-fluorouracil (5-FU) and its prodrugs capecitabine, gemcitabine,
cytosine arabinoside, fludarabine.
2. Inhibits production of folic acid from its inactive dihydrofolate form to the
active tetrahydrofolate (this is essential for transfer of methyl groups in DNA
synthesis). E.g. methotraxate.
They are cell-cycle specific (operating in the G1 – S phase), hence their toxicity reflects
effects on cells that proliferate quickly - bone marrow and GI mucosa.
Alkylating Agents:
These are NOT cell cycle-specific, and directly interfere with the DNA double strand
base pairs by chemically reacting with their structure, forming methyl cross-bridges.
These then prevent the two DNA strands coming apart in mitosis to form daughter DNA
fragments and division therefore fails. They are chemically diverse, and generate highly
reactive, positively charged intermediates, which combine with an electron-rich
nucleophilic group such as an amino acid, phosphate, or hydroxyl. E.g.
cyclophosphamide, chlorambucil, melphalan. Bifunctional alkylating agents from
covalent bonds between two different bases, resulting in interstrand and intrastrand crosslinks, whilst monofunctional alkylating agents cannot form cross-links but cause adducts
Intercalating Agents (also called Cytotoxics or Synthetics):
Specific to the S-phase of the cell-cycle. These act in a similar way to the alkylating
agents but rather than directly forming cross-strands in the DNA molecule they bind
between the base pair molecules: i.e. binding adenine to thymine, and cytosine to
guanine, again preventing DNA double strand from dividing. E.g. Platinum compounds
(cisplatin, oxaliplatin, carboplatin) act by binding specifically to guanosine, forming
DNA adducts that crosslink either within one DNA strand or across strands. Other
compounds active through DNA intercalation are the anthrax-cycline group of drugs
(adriamycin, epirubicin, doxorubicin).
Antimitotics (also called Spindle Poisons or Natural Products):
Specific to the M-phase of the cell-cycle. These act by preventing spindle formation,
which is essential in the sorting and moving of chromosomes following replication at the
end of mitosis. The drugs in the group are vinca alkaloids: vincristine, vinblastine,
vindesine. They have large volumes of distribution, indicating a high degree of tissue
binding, and are eliminated mainly by hepatic metabolism and biliary excretion.
Vincristine is the mainstay of treatment for childhood leukemia. Microtubule formation is
also affected by podophyllin and the taxane group of drugs ( paclitaxel, docetaxel), which
are cytotoxic through promoting the polymerization of tubulin, the building block of the
microtubule.
Topoisomerase Inhibitors:
Specific to the S-phase of the cell-cycle. Topoisomerase enzymes prevent DNA strands
from becoming tangled, by cutting DNA and allowing it to wind or unwind. The
inhibitors bind to and stabilise the DNA/topoisomerase cleavable complex, thus
preventing the relegation of DNA strands. Irreversible damage results when an advancing
DNA replication fork encounters the drug-stabilised cleavable complex, ultimately
leading to lethal double-stranded breaks.
Hormone Antagonists:
G2-phase specific & cytostatic in nature - hormone receptor antagonists bind to the
normal receptor for a given hormone and prevent its activation. The target recepetor may
be on the cell surface, as in the case of peptide and glycoprotein hormones, or it may be
intracellular, as in the case of steroid hormone receptors. E.g. Selective estrogen receptor
modulators (SERM's) - act as antagonists of the estrogen receptor and are used primarily
for the treatment and chemoprevention of breast cancer (tamoxifen)
Because of these modes of action, certain drugs require cells to be in specific phases of
the cell cycle to have any effect. Cytotoxic drugs are therefore further classified into:
- phase-specific drugs: acting only in a specific phase of the cell cycle (e.g.
antimetabolites during S-phase and vinca alkaloids in M-phase)
- cycle-specific drugs: requiring that cells be actively dividing and passing
through the cell cycle rather than being in the resting G0 phase – e.g. the
alkylating agents.
** Refer to Wk15 Blackboard Electronic Resources for a reading titled ‘Cancer
Chemotherapy’. Page 6-8 provide good summaries of these classes (which I have not
used in this info). These list factors such as drug administration, side effects, drug
interactions, resistance, and cancer types.
3. Outline differences between anticancer treatments and ‘typical’ drug therapy.
Anticancer treatments are intended to be toxic to the cancer cells, but innocuous to the
host. Their action is based in differences between the biochemistry (particularly DNA) of
the cancer cells and the host.
Cancer treatments such as chemotherapy cause a proportional reduction of affected cells,
rather than complete destruction, leading to the requirement for cycles of treatment. This
process is depicted below, starting with surgical removal of the tumor mass.
To be continued…
4. Describe the log cell kill hypothesis as it applies to the use of cytotoxic drugs.
The Cell Kill Hypothesis proposes that actions of cancer drugs follow first order kinetics:
a given dose kills a constant proportion of a tumor cell population (rather than a constant
number of cells).
Most applicable to the use of cancer drugs to treat acute leukemia’s and aggressive highgrade lymphomas. The growth rate is not constant (e.g., it slows as a tumor increases in
size) growth rates also vary significantly among tumor types. Tumor cell burden and the
population kinetics of the cancer cells are important determinants of the success of
chemotherapy, and directly determine the dosing schedule.
The magnitude of a tumor cell kill is a logarithmic function i.e., a 3-log-kill dose of an
effective drug will reduce the cancer cell load from 1012 cells to 109, or from 106 to 103
The example shows the effects of tumor burden, scheduling, dosing, and
initiation/duration of treatment on patient survival. The tumor burden in an untreated
patient would progress along the path described by the RED LINE - the tumor is
detected (using conventional techniques) when the tumor burden reaches 109 cells; the
patient is symptomatic at 1010-1011 cells, and dies at 1012 cells.
3 treatment options are shown:



DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log
kill) dosing and a late start prolongs survival but does not cure the patient (i.e.,
kill rate < growth rate)
LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2
log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate)
GREEN LINE: Early surgical removal of the primary tumour decreases the
tumour burden. Chemotherapy will remove persistent secondary tumours, and the
total duration of therapy does not have to be as long as when chemotherapy alone
is used.
See also this link for a relevant section on a paper from the Journal of Anticancer
Chemotherapy:
http://books.google.com.au/books?id=BNIBPy88u_sC&pg=PA1007&lpg=PA1007&dq=
log+cell+kill+hypothesis+cytotoxic&source=bl&ots=AU_N_sqa6j&sig=xCElMplgwKr
NXTBxT8gLWe5EFSw&hl=en&ei=9RIaSp2_BtWSkAXCpmg&sa=X&oi=book_result
&ct=result&resnum=2