This document summarizes the history and development of chemotherapy drugs for treating cancer. It begins by describing how mustard gas was accidentally discovered to suppress blood cell production and spur interest in using similar compounds to treat cancer. Early clinical trials in the 1940s showed temporary improvement in lymphoma patients treated with nitrogen mustards. Ongoing research since WWII has led to the development of many chemotherapy drugs from alkylating agents to anti-metabolites that work by damaging DNA and preventing cell division. The document discusses the mechanisms of several classes of chemotherapy drugs and provides examples of standard drug combinations used to treat various cancer types.

1. Drug discovery and clinical research

2. The first use of drugs to treat cancer was in the
early 20th century, although it was not originally
intended for that purpose. Mustard gas was used
as a chemical warfare agent during World War I
and was discovered to be a potent suppressor
of hematopoiesis (blood production). A similar
family of compounds known as nitrogen
mustards were studied further during World
War II at Yale University. It was reasoned that an
agent that damaged the rapidly growing white
blood cells might have a similar effect on cancer.

4.  Therefore, in December 1942, several patients
with advanced lymphomas (cancers of the
lymphatic system and lymph nodes) were given
the drug by vein, rather than by breathing the
irritating gas. Their improvement, although
temporary, was remarkable.Concurrently,
during a military operation in World War II,
following a German air raid on the Italian
harbour of Bari, several hundred people were
accidentally exposed to mustard gas, which had
been transported there by the Allied forces to
prepare for possible retaliation in the event of
German use of chemical warfare. The survivors
were later found to have very low white blood
cell counts.

5.  After WWII was over and the reports
declassified, the experiences converged and
led researchers to look for other substances that
might have similar effects against cancer. The
first chemotherapy drug to be developed from
this line of research was mustine. Since then,
many other drugs have been developed to treat
cancer, and drug development has exploded
into a multibillion-dollar industry, although the
principles and limitations of chemotherapy
discovered by the early researchers still apply.

6.  Cancer is the uncontrolled growth
of cells coupled with malignant behaviour:
invasion andmetastasis (among other
features). It is caused by the interaction
between geneticsusceptibility and
environmental factors. These factors lead to
accumulations ofgenetic
mutations in oncogenes (genes that promote
cancer) and tumor suppressor genes (genes
that help to prevent cancer), which gives cancer
cells their malignant characteristics, such as
uncontrolled growth.

8.  In the broad sense, most chemotherapeutic
drugs work by impairing mitosis (cell division),
effectively targeting fast-dividing cells. As these
drugs cause damage to cells, they are
termed cytotoxic. They prevent mitosis by
various mechanisms including damaging DNA
and inhibition of the cellular machinery
involved in cell division.[13][14] One theory as to
why these drugs kill cancer cells is that they
induce a programmed form of cell death known
as apoptosis.

9.  As chemotherapy affects cell division, tumors
with high growth rates (such as acute
myelogenous leukemia and the
aggressive lymphomas, including Hodgkin's
disease) are more sensitive to chemotherapy, as
a larger proportion of the targeted cells are
undergoing cell division at any time.
Malignancies with slower growth rates, such
asindolent lymphomas, tend to respond to
chemotherapy much more
modestly. Heterogeneic tumours may also
display varying sensitivities to chemotherapy
agents, depending on the subclonal
populations within the tumor.

10.  Alkylating agents are the oldest group of chemotherapeutics in
use today. Originally derived from mustard gas used in World
War I, there are now many types of alkylating agents in
use. They are so named because of their ability to alkylate many
molecules, including proteins, RNA and DNA. This ability to
bind covalently to DNA via their alkyl group is the primary
cause for their anti-cancer effects. DNA is made of two strands
and the molecules may either bind twice to one strand of DNA
(intrastrand crosslink) or may bind once to both strands
(interstrand crosslink). If the cell tries to replicate crosslinked
DNA during cell division, or tries to repair it, the DNA strands
can break. This leads to a form of programmed cell death
called apoptosis. Alkylating agents will work at any point in the
cell cycle and thus are known as cell cycle-independent drugs.
For this reason the effect on the cell is dose dependent; the
fraction of cells that die is directly proportional to the dose of
drug.

11.  Two DNA bases that are cross-linked by a nitrogen
mustard. Different nitrogen mustards will have
different chemical groups (R). The nitrogen
mustards most commonly alkylate the N7 nitrogen
of guanine (as shown here) but other atoms can be
alkylated.

12.  Alkylating agents are the oldest group of chemotherapeutics in
use today. Originally derived from mustard gas used in World
War I, there are now many types of alkylating agents in use. They
are so named because of their ability to alkylate many molecules,
including proteins, RNA and DNA. This ability to
bind covalently to DNA via their alkyl group is the primary cause
for their anti-cancer effects. DNA is made of two strands and the
molecules may either bind twice to one strand of DNA
(intrastrand crosslink) or may bind once to both strands
(interstrand crosslink). If the cell tries to replicate crosslinked
DNA during cell division, or tries to repair it, the DNA strands
can break. This leads to a form of programmed cell death
called apoptosis.Alkylating agents will work at any point in the
cell cycle and thus are known as cell cycle-independent drugs. For
this reason the effect on the cell is dose dependent; the fraction of
cells that die is directly proportional to the dose of drug.

13.  Anti-metabolites are a group of molecules that
impede DNA and RNA synthesis. Many of them
have a similar structure to the building blocks of
DNA and RNA. The building blocks
are nucleotides; a molecule comprising
a nucleobase, a sugar and a phosphate group. The
nucleobases are divided
into purines (guanine and adenine)
and pyrimidines(cytosine, thymine and uracil).
Anti-metabolites resemble either nucleobases or
nucleosides (a nucleotide without the phosphate
group), but have altered chemical groups.

14.  Deoxcytidine (left) and two anti-metabolite
drugs (centre and
right);Gemcitabine and Decitabine. The drugs
are very similar but they have subtle
differences in their chemical groups.

15.  These drugs exert their effect by either blocking
the enzymes required for DNA synthesis or
becoming incorporated into DNA or RNA. By
inhibiting the enzymes involved in DNA
synthesis, they prevent mitosis because the
DNA cannot duplicate itself. Also, after
misincorperation of the molecules into
DNA, DNA damage can occur and
programmed cell death (apoptosis) is induced.
Unlike alkylating agents, anti-metabolites are
cell cycle dependent. This means that they only
work during a specific part of the cell cycle, in
this case S-phase (the DNA synthesis phase).

16.  Breast cancer Cyclophosphamide, methotrexate, 5-fluorouracil
 Doxorubicin, cyclophosphamide
 Hodgkin's disease Mustine, vincristine, procarbazine, prednisolone
 Doxorubicin, bleomycin, vinblastine, dacarbazine
 Non-Hodgkin's lymphoma Cyclophosphamide, doxorubicin,
vincristine, prednisolone
 Germ cell tumor Bleomycin, etoposide, cisplatin
 Stomach cancer Epirubicin, cisplatin, 5-fluorouracil
 Epirubicin, cisplatin, capecitabine
 Bladder cancer Methotrexate, vincristine, doxorubicin, cisplatin
 Lung cancer Cyclophosphamide, doxorubicin, vincristine,
 Colorectal cancer 5-fluorouracil, folinic acid, oxaliplatin