MPHA5318

Pharmacotoxicology

Toxicity not addressed to specific

organs – Carcinogenesis 2

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 1. Alkylating agents
Alkylating agents = Electrophiles add alkly group (E.g.: CH3, C2H5) to negative centre of
DNA bases (GENOTOXIC)

Electron-rich centers in DNA. The targets most commonly attacked by electrophiles

are the phosphate groups, N7 of guanine and N3 of adenine (red); other targets are
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 1. Alkylating agents
Consequences of alkylation : Do not change the base-pairing (Chemical adduct)
: DNA strand break (single/double strand)
: Abasic
: Change base-pairing (mutation)

Alkylation of guanine. Ethylmethane sulfonate (EMS)

donates an ethyl group (blue) to the O6 oxygen,
creating O6-ethylguanine (right), which base-pairs with
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thymine instead of cytosine.
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 1. Alkylating agents
Some chemotherapy drugs alkylate the cancer cells to induce apoptosis. E.g.: Nitrogen
mustards (Cyclophosphamide, Chlorambucil, Melphalan). They produce DNA
adducts as well as induce the formation of DNA strand breaks. The alkylation of DNA
by nitrogen mustards requires the formation of highly reactive N-alkylazirdinium ions

Cyclophosphamide
Chlorambucil
Melphalan

Cyclophosphamide

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 1. Alkylating agents

Unfortunately, Alkylating chemotherapy drugs can actually cause

cancer (leukaemia).

Nitrogen mustards can produce a wide spectrum of mutations

including base pair substitutions (AT and GC) and deletions.

Acute non-lymphocytic leukemia, often associated with partial or

total deletions of chromosome 5 or 7, peaks in incidence about 4
years after therapy and may affect up to 5% of patients treated on
regimens containing alkylating drugs. It often is preceded by a
period of neutropenia or anaemia, and bone marrow morphology
consistent with myelodysplasia.

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 2. Azathioprine
Azathioprine acts as a prodrug for mercaptopurine to inhibit
amidophosphoribosyltransferase (an enzyme required for the synthesis
of DNA).

Azathioprine has once been developed as anticancer agent.

It is now widely used as an immunosuppressive agent during organ

transplantation.
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 2. Azathioprine
The major side effect of azathioprine is bone marrow
suppression, including leukopenia (common), thrombocytopenia
(less common), and/or anaemia (uncommon).

Azathioprine causes the accumulation of 6-thioguanine (6-TG) in

patients' DNA, which might trigger skin cancer when the patient is
later exposed to ultraviolet light.

Increase the risks of non-Hodgkin's lymphoma, hepatobiliary

carcinomas, and mesenchymal tumours

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 3. Chloramphenicol
• An antibiotic produced by Streptomyces venezuelae (gram positive
bacteria).

• Chloramphenicol has a wide range activity that includes Gram+,

Gram-, aerobic and anaerobic bacteria

• Typhoid Fever
• Bacterial Meningitis
• Anaerobic Infections
• Rickettsial Diseases
• Brucellosis

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 3. Chloramphenicol
Mechanism of Action
Chloramphenicol is a bacteriostatic by inhibiting protein synthesis. It
prevents protein chain elongation by inhibiting the peptidyl
transferase activity of the bacterial ribosome.

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 3. Chloramphenicol
Toxicity
- Aplastic anaemia (most serious)-RARE but FATAL
The effect occurs weeks or months after treatment has been stopped

For this reason, chloramphenicol is now reserved for treatment of life-

threatening infections (e.g., meningitis, rickettsial infections) in patients
who cannot take safer alternatives because of resistance or allergies.

- Bone marrow suppression (Anaemia, leukopenia, or

thrombocytopenia).

- Leukaemia

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 4. Diethylstilbestrol
• Diethylstilbestrol (DES) is a synthetic
oestrogen. It was prescribed to pregnant
women (1940-1971) to prevent
miscarriage, premature labour, and
related complications of pregnancy .

• Prenatal (before birth) DES exposure = ↑

risk of a type of cancer of the cervix and
vagina (clear cell adenocarcinoma) in
women (15-22 years old).

• DES is now known to be an endocrine-

disrupting chemical, one of a number of
substances that interfere with
the endocrine system to cause cancer,
birth defects, and other developmental
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 5. Oestrogen
• Estradiol is the most important estrogen produced by the
ovaries. Other estrogens (estrone, estriol) may be weaker, but in
principle have the same effect.

• Hormone replacement therapy to alleviate menopause

symptoms or osteoporosis.

• Oral contraceptive pills

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 5. Oestrogen
Oestrogen is involved in breast cancers, ovary cancer and uterine cancer

How?????????
1) Oestrogen encourages certain cell
to divide more often. More cell
divisions means more DNA errors.

2) Oestrogen turns on certain genes

inside cells at the wrong time– E.g.:
Preventing damaged cells from
dying.

3) Recent laboratory evidence (2009)

that oestrogen can directly bind to,
and damage, DNA

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 6.Phenacetin

◼ Phenacetin is useful for pain and fever (Phenacetin is metabolised

in the body as Acetaminophen).

◼ Phenacetin (1887) was used for decades, but in the 1970s it was
implicated in cases of liver, nephrotoxicity and urothelial
neoplasms, especially urothelial carcinoma of the renal pelvis
(Removed from the market in 1983).

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 7. Phenytoin
• First-line for partial seizures; some use for tonic-
clonic seizures (Prevention)

• Fosphenytoin: Prodrug for Phenytoin, used for

IM injection

• There have been a number of reports suggesting a relationship

between phenytoin and the development of lymphadenopathy
(local or generalized) including benign lymph node hyperplasia,
pseudolymphoma, lymphoma, and Hodgkin’s disease but
INCONCLUSIVE.

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 8. Thorotrast
• Thorotrast is a suspension containing particles of
the radioactive compound thorium dioxide (ThO2), a radiocontrast
agent in medical radiography in the 1930s and 1950s (produced
excellent images)

• Unfortunately, thorium is retained in the body, and it is

radioactive, emitting harmful alpha radiation as it decays (Half life
= 22 YEARS!!).

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 Thorotrast
• Exposure to Thorotrast has been linked to angiosarcoma (cancer of
the inner lining of blood vessels) and cholangiocarcinoma (cancer
of epithelial cells in the bile duct) in the liver.

• The compound accumulates in Kupffer cells (specialised

macrophages in the liver) and emits radioactivity throughout its
extended half-life.

• One study of Danish patients exposed to Thorotrast found that the

risk for bile duct and gallbladder cancers was increased 14-fold and
that for liver cancers more than 100-fold (Andersson and Storm,
1992).

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