At a glance- classification, mechanism, uses, and toxicity of anticancer drugs

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Anticancer Drugs
Learning Objectives
❏ Define the mechanisms of anticancer drugs
❏ Demonstrate an understanding of the toxicity of anticancer drugs
PRINCIPLES
Log-Kill Hypothesis- Cytotoxic actions of anticancer drugs follow first-order kinetics: They kill a fixed
percentage of tumor cells, not a fixed number, which is one rationale for drug combinations.
Growth Fraction- Cytotoxic drugs are more effective against tumors that have a high growth
fraction (large percentage actively dividing). Normal cells with high growth fraction (e.g., bone
marrow) are also more sensitive to anticancer drugs.

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CANCER
Cancer is a disease of cells characterized by Progressive, Persistent, Perverted (abnormal),
Purposeless and uncontrolled Proliferation of tissues. Both normal as well as cancerous cells must
pass through the following phases of cell cycle (Fig. 1).
1. G1 phase (presynthetic phase): Synthesis of enzymes and other cellular components needed for
DNA synthesis.
2. Synthetic phase (S phase): DNA synthesis takes place.
3. G2 phase (premitotic phase): Synthesis of cellular components for mitosis (proteins and RNA
synthesis).
4. Mitotic phase (M phase): Mitotic cell division takes place.
5. G0 phase (resting phase): Cells stop dividing temporarily or permanently.

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Fig. 1

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Classification of Anticancer Drugs (AT A GLANCE)
1. Alkylating agents
a. Nitrogen mustards: Cyclophosphamide
b. Alkyl sulphonate: Busulphan.
c. Nitrosoureas: Carmustine, lomustine.
d. Platinum-containing compounds: Cisplatin, carboplatin.
2. Antimetabolites
a. Folate antagonist: Methotrexate.
b. Purine antagonists: 6-Mercaptopurine (6-MP), 6-thioguanine (6-TG).
c. Pyrimidine antagonists: 5-Fluorouracil (5-FU).
3. Vinca alkaloids: Vinblastine, vincristine.
4. Taxanes: Paclitaxel, docetaxel.
5. Epipodophyllotoxins: Etoposide, teniposide.
6. Camptothecins: Topotecan, irinotecan.
7. Antibiotics: Actinomycin D, bleomycin, mitomycin C, doxorubicin, daunorubicin.
8. Enzymes: L-Asparaginase.
9. Miscellaneous agents: Hydroxyurea, imatinib.
10. Hormones and antagonists: Glucocorticoids, estrogens, antioestrogens, progestins, androgens and antiandrogens.

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Mechanism of Action of Anticancer Drugs (AT A GLANCE)

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Toxicity of Anticancer Drugs (Cytotoxic Drugs)
While destroying cancer cells, anticancer drugs also affect rapidly proliferating normal cells. Bone
marrow, skin, hair, gastrointestinal mucosa, reticuloendothelial (RE) system, gonads, foetus, etc.
are most severely affected.
1. General toxicity
a. Bone marrow suppression: It manifests as leukopaenia, agranulocytosis, thrombocytopaenia
and aplastic anaemia. In such patients, infection and bleeding are common.
Ameliorated/reduced by:
i. Platelet transfusion
ii. Granulocyte colony-stimulating factor (G-CSF)
iii. Erythropoietin

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iv. Bone marrow transplantation
v. Using bone marrow-sparing drugs if possible (e.g. L-asparaginase, bleomycin, cisplatin,
vincristine).
b. Immunosuppression: Decreased lymphocytes result in immunosuppression. Such patients are
prone for opportunistic infections with fungi, bacteria, viruses, parasites (P. jiroveci, Candida,
CMV, etc.).
c. Oral cavity: Mucositis, oral ulceration, stomatitis, xerostomia, infections (Candida, herpes, etc.),
gingival bleeding and mucosal petechiae due to thrombocytopaenia. Mucositis is ameliorated
by oral cooling using ice chips, topical agents like benzydamine (rinse or spray), 2% viscous
lignocaine and chlorhexidine mouth rinses.
d. GIT: Nausea and vomiting are due to central action (stimulation of CTZ) and peripheral action in

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GI tract. Most of the cytotoxic drugs cause vomiting. Cisplatin has the most emetogenic
potential. 5-HT3 antagonists such as ondansetron and granisetron are the commonly used
antiemetics. The other antiemetics are metoclopramide and dexamethasone. Stomatitis, oral
mucositis, diarrhoea, GI bleeding and ulcers are due to necrosis of rapidly dividing epithelial
cells of gut mucosa.
e. Skin and hair: Alopecia (loss of hair) is due to the damage to hair follicles. Alopecia is usually
reversible on stoppage of therapy. Dermatitis and skin rashes too can occur.
f. Gonads: Cytotoxic drugs also affect gonadal cells and cause oligozoospermia and infertility in
males, and amenorrhoea and infertility in females.
g. Foetus: Administration of cytotoxic drugs during pregnancy usually causes abortion or
teratogenic effects.

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h. Hyperuricaemia: Gout and urate stones in the urinary tract are due to excessive cell destruction.
They are prevented by good hydration, allopurinol and corticosteroids.
i. Hypercalcaemia: It may be either due to the malignancy or certain anticancer drugs. It is
treated with adequate hydration, bisphosphonates, corticosteroids, etc.
j. Carcinogenicity (secondary malignancy): These drugs may rarely cause secondary cancers in
some patients, e.g. development of leukaemia in patients with prolonged use of alkylating
agents.
k. Mutagenicity.

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2. Specific toxicity
a. Haemorrhagic cystitis with cyclophosphamide: Ameliorated by administering mesna systemically and
acetylcysteine locally.
b. Megaloblastic anaemia with methotrexate: Ameliorated by folinic acid/leucovorin/citrovorum factor.
c. Stomatitis with methotrexate.
d. Nephrotoxicity with cisplatin: Infusion of saline and mannitol reduces the incidence of
nephrotoxicity.
e. Ototoxicity with cisplatin.
f. Neuropathy with vincristine and paclitaxel.
g. Pulmonary fibrosis and pigmentation of skin with busulphan and bleomycin.
h. Cardiotoxicity with doxorubicin and daunorubicin.

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CHEMOMAN

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IMPORTANT ANTICANCER DRUGS
Alkylating Agents
All alkylating agents have alkyl group(s) and are capable of introducing these groups into nucleophilic
sites on DNA bases through the formation of covalent bonds. Alkylating agents are CCNS drugs. They
also have radiomimetic effect.

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Nitrogen Mustards
Cyclophosphamide
Cyclophosphamide is a prodrug and is activated in liver (Fig. 2).

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Fig.2
The final active metabolites derived from cyclophosphamide are phosphoramide mustard and acrolein.
Phosphoramide mustard produces cytotoxic effect and acrolein is responsible for haemorrhagic
cystitis.

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Cyclophosphamide is administered orally or intravenously. The metabolites are excreted mainly in
urine.
Adverse effects
General toxicity (see previous slides). The specific toxicity of cyclophosphamide is severe haemorrhagic
cystitis. It is associated with dysuria and haematuria due to irritation of bladder mucosa by acrolein.
It is a dose-limiting toxicity and can be reduced by adequate hydration and co-administration of i.v.
mesna (2-mercapto-ethane-sulphonate). Mesna is also excreted in urine where it binds and inactivates
acrolein, thus preventing haemorrhagic cystitis.
Uses
Cyclophosphamide is used in combination with other anticancer agents in the treatment of
lymphomas, chronic lymphocytic leukaemia, breast cancer, etc. It also has powerful
immunosuppressant effect; hence, it is useful in rheumatoid arthritis, nephrotic syndrome and to

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prevent as well as to treat graft rejection during organ transplantation.
Ifosfamide is a congener of cyclophosphamide and is administered intravenously. It is useful in the
treatment of testicular cancer and sarcomas.
Alkyl Sulphonates
Busulphan
It depresses bone marrow with selective action on myeloid series. It was the preferred drug for
chronic myeloid leukaemia (CML). The common side effects are pigmentation of the skin, interstitial
pulmonary fibrosis and hyperuricaemia.
Nitrosoureas
Carmustine and lomustine are highly lipid soluble drugs; hence, they reach high concentration in the
CSF. Nitrosoureas are mainly used in brain tumours.

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Platinum-containing Compounds
Cisplatin
It is a heavy-metal complex with highly effective antineoplastic activity. It is a CCNS drug and acts on
both dividing as well as resting cells. Cisplatin is administered intravenously. It is highly bound to
plasma proteins and gets concentrated in kidney, liver, intestines and testes. It poorly penetrates BBB
and is slowly excreted in urine.

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Cisplatin is highly effective in the treatment of testicular, ovarian, endometrial and bladder cancer.
It is also used in lung and oesophageal cancer.
Adverse effects
Cisplatin is the most emetogenic anticancer drug. Vomiting can be controlled by 5-HT3 antagonists
such as ondansetron or granisetron.

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Nephrotoxicity: It can be minimized by proper hydration and chloride diuresis. Ototoxicity
with hearing loss can occur and is severe with repeated doses.
Electrolyte disturbances: Hypokalaemia, hypocalcaemia and hypomagnesaemia are common.
Neuropathy is commonly seen with higher doses. Rarely, anaphylactic shock may occur. Cisplatin has
mutagenic, teratogenic and carcinogenic properties.
Antimetabolites
Folate Antagonist
Methotrexate (Mtx)
Methotrexate is one of the most commonly used anticancer drugs. It is a cell cycle specific (CCS) drug
and acts during S phase of the cell cycle. It has antineoplastic, immunosuppressant and anti-
inflammatory effects.

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Methotrexate structurally resembles folic acid. It competitively inhibits dihydrofolate reductase enzyme
and prevents the conversion of DHFA to THFA, thus depleting the intracellular THFA. Tetrahydrofolic
acid is necessary for the synthesis of purines and thymidylate, which, in turn, are necessary for DNA and
RNA synthesis.
Methotrexate is well absorbed after oral administration and can also be given i.m., i.v. or intrathecally.
It is bound to plasma proteins, poorly crosses the BBB, and most of the drug is excreted unchanged in
urine.
Methotrexate is the drug of choice for choriocarcinoma. It is also used in acute leukaemias, Burkitt’s
lymphoma and breast cancer.
Adverse effects
See general toxicity (see previous slides). Other adverse effects are megaloblastic anaemia, stomatitis,
pancytopaenia, hepatic fibrosis, etc.

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Folinic acid rescue/leucovorin rescue
The toxic effects of methotrexate on normal cells can be minimized by giving folinic acid. Availability of
folinic acid has helped the use of very high doses of methotrexate for better antineoplastic effect.
After a few hours of methotrexate therapy, leucovorin is given. Folinic acid is the active coenzyme form.
It bypasses the block produced by methotrexate and rapidly reverses the toxicity. This method is called
as leucovorin rescue/folinic acid rescue.
Purine Antagonists: 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG)
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG) are activated to their ribonucleotides, which
inhibit purine ring biosynthesis and nucleotide interconversion. They are CCS drugs that act in S phase
of cell cycle. 6-MP also has immunosuppressant action.
6-MP is administered orally and has poor penetration through the BBB. It is metabolized by xanthine

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oxidase and its metabolite is excreted in urine.
Allopurinol interferes with the metabolism of 6-MP by inhibiting the enzyme xanthine oxidase
and increases the antineoplastic effect of 6-MP. Therefore, allopurinol is frequently used in
cancer patients receiving chemotherapy to prevent hyperuricaemia and to reduce the dose of
6-MP, thus reducing its toxicity. 6-MP is used mainly in acute lymphocytic leukaemia. Bone
marrow depression is the major adverse effect of 6-MP.

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Pyrimidine Antagonists
Fluorouracil (5-FU)
5-Fluorouracil interferes with DNA synthesis. It is used in gastrointestinal tract (GIT), breast,
ovary, skin, recurrent/metastatic salivary gland tumours, etc.
Plant Products
Vinca Alkaloids
Vinblastine and vincristine are derived from the periwinkle plant. They are CCS agents and act
during M phase of cell cycle. Vinblastine and vincristine have the same mechanism of action
but differ in antitumour spectrum and toxicity (Table 1).

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Table 1

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Taxanes
Paclitaxel is a taxane derived from the bark of the Western yew tree. Docetaxel is a newer taxane.
Paclitaxel is administered by i.v. infusion. It is useful in advanced breast, ovarian, lung, oesophageal and
bladder cancer. The unwanted effects are bone marrow suppression, peripheral neuropathy, myalgia
and hypersensitivity reactions.

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Anticancer Antibiotics
Mechanism of action
Anticancer antibiotics have direct action on DNA and interfere with cell division.
Bleomycin
It is used in squamous cell carcinoma of the skin, carcinoma of oral cavity, head and neck cancer. Its
main side effects are hyperpigmentation of skin and pulmonary fibrosis. There is very little bone
marrow suppression (spares bone marrow).
Doxorubicin and Daunorubicin
Daunorubicin is effective in acute leukaemias; doxorubicin is active against solid tumours. The side
effects are bone marrow suppression, GI disturbances and cardiomyopathy with CCF, hypotension or

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arrhythmias.
Actinomycin D
It is administered intravenously. It is used in the treatment of Wilm’s tumour and choriocarcinoma.
Bone marrow suppression and gastrointestinal side effects are prominent.
Hormonal Agents
Hormones produce only palliative effects in cancer.
1. Glucocorticoids: Because of their marked lympholytic action, they are used in acute leukaemias and
lymphomas. Apart from this effect, glucocorticoids:

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a. have antiinflammatory effect, decrease oedema associated with the tumour.
b. produce feeling of well-being.
c. suppress hypersensitivity reaction due to certain anticancer drugs.
d. control hypercalcaemia.
e. increase the antiemetic effect of ondansetron/granisetron/metoclopramide.
Because of the above effects, glucocorticoids are useful in the treatment of various cancers.
2. Others are oestrogens, progestins, tamoxifen, and antiandrogens, finasteride, etc.

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QUICK RECALL QUESTIONS
What is the name of the cyclophosphamide and ifosfamide urotoxic metabolite that is responsible
for causing hemorrhagic cystitis?
ACROLEIN
What is the name of the antidote that binds to and inactivates acrolein, thereby preventing
hemorrhagic cystitis in patients receiving cyclophosphamide or ifosfamide chemotherapy?
MESNA

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What is the mechanism of action of methotrexate?
Inhibits dihydrofolate reductase (DHFR), thereby decreasing the con-version of folic acid to
tetrahydro-folic acid (active form); since THF is involved in DNA synthesis, less THF means less DNA
synthesis and less cell replication
What are the adverse effects of methotrexate?
Stomatitis; bone marrow suppression (BMS); megaloblastic anemia; urticaria; alopecia; nausea;
vomiting; diarrhea; nephrotoxicity; hepatotoxicity; pulmonary toxicity; neurotoxicity

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In a patient taking methotrexate, what drug is used as a “rescue medication” to reverse
myelosuppression?
Leucovorin, which acts as an active form of folic acid (replenishing the folate pool) that has bypassed
the inhibited DHFR and is more readily taken up by normal cells than by malignant cells
Give examples of anticancer alkylating agents:
Cyclophosphamide; ifosfamide; nitrosoureas (carmustine, lomustine); cisplatin; carboplatin

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Are the anticancer alkylating chemotherapeutic agents CCS?
NO
What is the mechanism of action of anticancer alkylating agents?
Covalently bind (alkylation) to DNA, leading to cross-linked and dysfunctional DNA strands
What is the clinical use of nitrosoureas?
Brain tumors (lipophilic so cross the blood–brain barrier)

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Give examples of anticancer mitotic inhibitors:
Paclitaxel; Docetaxel
Which plant is paclitaxel a derivative of?
Bark of the Western yew tree
What is the mechanism of action of paclitaxel?
Binds to tubulin and increases polymerization and stabilization of the microtubule structure, thereby
preventing depolymerization

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Give examples of anticancer antibiotics:
Doxorubicin; daunorubicin; dactinomycin; bleomycin
Which phase of the cell cycle is bleomycin specific for?
G2