Hi, this is a well-written summary covering all the contents of CHEM60004, a third year chemistry course at Imperial College London. It covers the background knowledge of cancer, mechanism of action of different chemotherapies including alkylating (crosslinking) agents, antimetabolites, antitubuli...
Background knowledge of cancer
Cancer definition: A tumour (or neoplasm) is an abnormal tissue mass or growth that
results from neoplasia, a state in which the control mechanisms governing cell growth
become deficient, leading to cell proliferation. Cancer is usually ageing related.
There are more than 100 different types of cancers, with more subtypes within the same
organs. The genetic drivers of same cancers can be different. Cancer is a complex disease
with no single drug treatment and requires more personalised medicine.
Genetic reasons: Cancer is caused by a succession of multiple genetic mutations, each
conferring one or another type of growth advantage. The initial genetic alteration usually
alters DNA-repair pathways by DNA-damage events, conferring genomic instability and
providing the cancer with an evolutionary advantage. Genomic instability is key for tumours
because in normal cells, even single mutations are very rare, with multiple mutations
unlikely to occur within a human lifespan. Such changes might result in the generation of
non-functional proteins. There can be genetic predisposition on oncogene/tumour
suppressor mutation.
Epigenetic reasons: DNA is wrapped around histone proteins. Different chromatin
packaging allows different expressions of genes. Epigenetic changes do not involve any
alteration of genetics but affects the expression level of the gene by changing the
accessibility of the promoter-region to polymerases. This might result in over-expression of
an oncogene (when mutated or expressed at high levels, helps turn a normal cell into a
cancer cell) or down-regulation of a tumor suppressor (protects a cell from one step on the
path to cancer. Its mutation causes a loss/reduction in its function, so the cell can progress
to cancer, usually in combination with other genetic changes).
Classic, broad-spectrum chemotherapies
Pros: Highly effective on a variety of cancers. Allow quick response and tumour shrinking
pre-surgery. Responsive (mostly) independent from patient genetic background. They (still)
save lives.
Cons: Side effects are severe.
1. Alkylating (crosslinking) agents
Definition&General MOA: Electrophilic molecules that attack nucleophilic sites on DNA
(mainly Guanine bases, Guanine N7 is one of the most nucleophilic sites of DNA), generate
covalent bonds with DNA. They usually have two electrophilic sites to create inter or intra
strand crosslink DNA damage, therefore causing loss of genetic information and impairing
cellular replication. Both inter and intra strand crosslinks can be repaired with DNA repair
machineries, therefore cancer presenting deficiencies on specific DNA repair pathways
might be targeted selectively. They need to be stable enough to reach cellular DNA but also
reactive enough to promptly react with DNA.
Intra-strand cross-links: formed between two adjacent nucleotides within the same DNA
strand. Can be repaired by Nucleotide Excision Repair (NER) or Base Excision Repair
(BER) (act only on one base). Less toxic as relatively easy for a cancer cell to deal with
because can be repaired without causing loss of genetic information. The original sequence
can be copied back from the non-damaged strand.
, Inter-strand cross-links: formed between nucleotides on opposite strands of DNA. Can be
repaired by Homologous Recombination (HR) (BRCA genes). Far more toxic than single-
stranded DNA breaks as they prevent double helical unwinding and create double stranded
DNA breaks.
Nitrogen mustard: The molecule is first activated through SN2 nucleophilic attack by its
own nitrogen lone pair to form an aziridinium ion with elimination of chloride. The ion then
reacts with an N7-atom of a guanine base in the major groove of DNA through a SN1-like
nucleophilic substitution reaction and form a covalent bond. This process is repeated with
the second chloroethyl group and another guanine N7-atom to form a more toxic inter-
strand cross-link which prevents dsDNA unwinding, curbs DNA replication and leads to cell
death. Since it causes inter-strand crosslink, it can treat Homologous Recombination (HR) /
BRCA genes deficient cancer. MDR-related resistance, Cancer cells reduce the activity of
nitrogen mustards by elevating the level of highly nucleophilic glutathione which forms
adducts with nitrogen mustards and causes them to become non-electrophilic and unable to
react with DNA.
Sulfur based mustard gas too toxic as the sulphur lone pair is too reactive. The accessibility
of the nitrogen lone pair is key for the formation of reactive aziridinium ion. Chlorine is a
good leaving group for SN2 nucleophilic substitution. Linker length between electrophilic
sites is key to optimize inter-strand crosslinks and 2 carbon based nitrogen mustard
scaffolds are ideal. Different substituents can be added on nitrogen to control reactivity and
solubility.
Cyclophosphamide: Aromatic ring acts as an electron sink, withdrawing electrons from the
nitrogen atom to reduce reactivity so that they can reach their target DNA before being
deactivated by reaction with collateral nucleophiles and can be administered orally with
milder side-effects. Formation of phosphoramide mustard active agent through biooxidation
in the liver. Acrolein side-product causes hemorrhagic cystitis, which is avoided by sacrificial
nucleophile mesna. Dosed by IV or orally. Treatment of solid tumours of the breast, ovary,
various sarcomas, chronic lymphocytic leukemia (CLL) and lymphomas.
Chlorambucil: The carboxyl group is electronically insulated from the aromatic ring by a
number of methylene groups to increase solubility while maintaining reactivity. Treatment of
chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (NHL) and non-Hodgkin
lymphoma (NHL).
Linking a crosslinking agent to molecular recognition moieties or hairpin polyamides can
direct mustards to specific DNA sequences and accumulate alkylation at specific sites to
increase specificity and decrease off-target binding. However, delivery issues of polyamide
chains reduce clinically applicability.
Cis-platin: Two chlorine leaving groups need to be in cis position to be substituted by the
N7
atoms of two adjacent guanine bases to form intra-strand cross-links. Lower Cl -
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