Anticancer Drugs

Chemotherapy of Malignant Tumors
A tumor (neoplasm) consists of cells
that proliferate independently of the
body’s inherent “building plan.” A malignant
tumor (cancer) is present when
the tumor tissue destructively invades
healthy surrounding tissue or when dislodged
tumor cells form secondary tumors
(metastases) in other organs. A
cure requires the elimination of all malignant
cells (curative therapy). When
this is not possible, attempts can be
made to slow tumor growth and thereby
prolong the patient’s life or improve
quality of life (palliative therapy).
Chemotherapy is faced with the problem
that the malignant cells are endogenous
and are not endowed with special
metabolic properties.
Cytostatics (A) are cytotoxic substances
that particularly affect proliferating
or dividing cells. Rapidly dividing
malignant cells are preferentially injured.
Damage to mitotic processes not
only retards tumor growth but may also
initiate apoptosis (programmed cell
death). Tissues with a low mitotic rate
are largely unaffected; likewise, most
healthy tissues. This, however, also applies
to malignant tumors consisting of
slowly dividing differentiated cells. Tissues
that have a physiologically high
mitotic rate are bound to be affected by
cytostatic therapy. Thus, typical adverse
effects occur:
Loss of hair results from injury to
hair follicles; gastrointestinal disturbances,
such as diarrhea, from inadequate
replacement of enterocytes
whose life span is limited to a few days;
nausea and vomiting from stimulation of
area postrema chemoreceptors ;
and lowered resistance to infection from
weakening of the immune system .
In addition, cytostatics cause bone
marrow depression. Resupply of blood
cells depends on the mitotic activity of
bone marrow stem and daughter cells.
When myeloid proliferation is arrested,
the short-lived granulocytes are the first
to be affected (neutropenia), then blood
platelets (thrombopenia) and, finally,
the more long-lived erythrocytes (anemia).
Infertility is caused by suppression
of spermatogenesis or follicle maturation.
Most cytostatics disrupt DNA metabolism.
This entails the risk of a potential
genomic alteration in healthy
cells (mutagenic effect). Conceivably,
the latter accounts for the occurrence of
leukemias several years after cytostatic
therapy (carcinogenic effect). Furthermore,
congenital malformations are to
be expected when cytostatics must be
used during pregnancy (teratogenic effect).
Cytostatics possess different mechanisms
of action.
Damage to the mitotic spindle.
The contractile proteins of the spindle
apparatus must draw apart the replicated
chromosomes before the cell can divide.
This process is prevented by the
so-called spindle poisons (see also colchicine)
that arrest mitosis at
metaphase by disrupting the assembly
of microtubules into spindle threads.
The vinca alkaloids, vincristine and vinblastine
(from the periwinkle plant, Vinca
rosea) exert such a cell-cycle-specific
effect. Damage to the nervous system is
a predicted adverse effect arising from
injury to microtubule-operated axonal
transport mechanisms.
Paclitaxel, from the bark of the pacific
yew (Taxus brevifolia), inhibits disassembly
of microtubules and induces
atypical ones. Docetaxel is a semisynthetic
derivative.


Inhibition of DNA and RNA synthesis
(A). Mitosis is preceded by replication
of chromosomes (DNA synthesis)
and increased protein synthesis (RNA
synthesis). Existing DNA (gray) serves as
a template for the synthesis of new
(blue) DNA or RNA. De novo synthesis
may be inhibited by:
Damage to the template (1). Alkylating
cytostatics are reactive compounds
that transfer alkyl residues into
a covalent bond with DNA. For instance,
mechlorethamine (nitrogen mustard) is
able to cross-link double-stranded DNA
on giving off its chlorine atoms. Correct
reading of genetic information is thereby
rendered impossible. Other alkylating
agents are chlorambucil, melphalan,
thio-TEPA, cyclophosphamide (p. 300,
320), ifosfamide, lomustine, and busulfan.
Specific adverse reactions include
irreversible pulmonary fibrosis due to
busulfan and hemorrhagic cystitis
caused by the cyclophosphamide metabolite
acrolein (preventable by the
uroprotectant mesna). Cisplatin binds to
(but does not alkylate) DNA strands.
Cystostatic antibiotics insert themselves
into the DNA double strand; this
may lead to strand breakage (e.g., with
bleomycin). The anthracycline antibiotics
daunorubicin and adriamycin (doxorubicin)
may induce cardiomyopathy. Bleomycin
can also cause pulmonary fibrosis.
The epipodophyllotoxins, etoposide
and teniposide, interact with topoisomerase
II, which functions to split,
transpose, and reseal DNA strands
(p. 274); these agents cause strand
breakage by inhibiting resealing.
Inhibition of nucleobase synthesis
(2). Tetrahydrofolic acid (THF) is required
for the synthesis of both purine
bases and thymidine. Formation of THF
from folic acid involves dihydrofolate
reductase (p. 272). The folate analogues
aminopterin and methotrexate (amethopterin)
inhibit enzyme activity as
false substrates. As cellular stores of THF
are depleted, synthesis of DNA and RNA
building blocks ceases. The effect of
these antimetabolites can be reversed
by administration of folinic acid (5-formyl-
THF, leucovorin, citrovorum factor).
Incorporation of false building
blocks (3). Unnatural nucleobases (6-
mercaptopurine; 5-fluorouracil) or nucleosides
with incorrect sugars (cytarabine)
act as antimetabolites. They inhibit
DNA/RNA synthesis or lead to synthesis
of missense nucleic acids.
6-Mercaptopurine results from biotransformation
of the inactive precursor
azathioprine (p. 37). The uricostatic allopurinol
inhibits the degradation of 6-
mercaptopurine such that co-administration
of the two drugs permits dose
reduction of the latter.
Frequently, the combination of cytostatics
permits an improved therapeutic
effect with fewer adverse reactions.
Initial success can be followed by
loss of effect because of the emergence
of resistant tumor cells. Mechanisms of
resistance are multifactorial:
Diminished cellular uptake may result
from reduced synthesis of a transport
protein that may be needed for
membrane penetration (e.g., methotrexate).
Augmented drug extrusion: increased
synthesis of the P-glycoprotein
that extrudes drugs from the cell (e.g.,
anthracyclines, vinca alkaloids, epipodophyllotoxins,
and paclitaxel) is reponsible
for multi-drug resistance
(mdr-1 gene amplification).
Diminished bioactivation of a prodrug,
e.g., cytarabine, which requires
intracellular phosphorylation to become
cytotoxic.
Change in site of action: e.g., increased
synthesis of dihydrofolate reductase
may occur as a compensatory
response to methotrexate.
Damage repair: DNA repair enzymes
may become more efficient in repairing
defects caused by cisplatin.