Anticancer Drugs

Pharmacology Team
Naim Kittana, Suhaib Hattab, Ansam Sawalha, Adham Abu Taha,
Waleed Sweileh, Ramzi Shawahneh

Faculty of Medicine & Health Sciences

An-Najah National University 1
 Introduction

• Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis

in the cancer cells that can arrest a tumor’s progression.

• The attack is generally directed toward DNA or against metabolic sites

essential to cell replication

• Ideally, these drugs should interfere only with cellular processes that are
unique to malignant cells.

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 Introduction

• Unfortunately, most currently available anticancer drugs do not

specifically recognize neoplastic cells

• Therefore, almost all antitumor agents have a steep dose–response curve

for both therapeutic and toxic effects

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Principles of cancer chemotherapy
TREATMENT STRATEGIES

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 Goals of treatment

• The ultimate goal of chemotherapy is a cure (that is, long-term, disease-

free survival).

• A true cure requires the eradication of every neoplastic cell.

• If a cure is not attainable, then the goal becomes control of the disease
(stop the cancer from enlarging and spreading) to extend survival and
maintain the best quality of life.

• Thus, the individual maintains a “near-normal” existence, with the cancer

being treated as a chronic disease.

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 Goals of treatment

In either case, the neoplastic cell burden is initially reduced (debulked) by:

• Either surgery and/or by radiation

• Followed by:
 Chemotherapy,
 Immunotherapy: using biological modifiers or
 a combination of these treatment modalities

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 Goals of treatment

• In advanced stages of cancer, the likelihood of controlling the cancer is

not realistic and the goal is palliation (alleviation of symptoms and
avoidance of life-threatening toxicity).

• This means that chemotherapeutic drugs may be used to relieve

symptoms caused by the cancer and improve the quality of life

• In this case the drugs may not extend survival.

• The goal of treatment should always be kept in mind, as it often influences

treatment decisions

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Goals of treatment

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Effects of various treatments on the cancer cell burden in a
hypothetical patient

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 Indications for treatment

• Chemotherapy is sometimes used when neoplasms are disseminated and

are not amenable to surgery.

• Adjuvant chemotherapy: when chemotherapy is used as a supplemental

treatment to attack micro-metastases following surgery and radiation

• Neoadjuvant chemotherapy: when chemotherapy is given prior to the

surgical procedure in an attempt to shrink the cancer

• Maintenance chemotherapy: Chemotherapy given in lower doses to assist

in prolonging remission

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 Tumor susceptibility and the growth cycle

• The fraction of tumor cells that are in the

replicative cycle (“growth fraction”)
influences their susceptibility to most
cancer chemotherapeutic agents.

• Rapidly dividing cells are generally more

sensitive to chemotherapy, whereas slowly
proliferating cells are less sensitive

• In general, non-dividing cells (those in the

G0 phase) usually survive the toxic effects
of many of these agents.

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 Tumor susceptibility and the growth cycle

Cell cycle specificity of drugs:

• Both normal cells and tumor cells go through growth cycles.

• However, the number of cells that are in various stages of the cycle may
differ in normal and neoplastic tissues.

• Chemotherapeutic agents that are effective only against replicating cells

are said to be cell cycle specific

• The other agents are said to be cell cycle nonspecific.

• The nonspecific drugs, although having generally more toxicity in cycling

cells, are also useful against tumors that have a low percentage of
replicating cells.

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Tumor susceptibility and the growth cycle

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 Tumor susceptibility and the growth cycle

Tumor growth rate:

• The growth rate of most solid tumors in vivo is initially rapid, but growth
rate usually decreases as the tumor size increases

• This is due to the unavailability of nutrients and oxygen caused by

inadequate vascularization and lack of blood circulation.

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 Tumor susceptibility and the growth cycle

Tumor growth rate:

Tumor burden can be reduced through:
• Surgery

• Radiation, or
• by using cell cycle–nonspecific drugs to promote the remaining cells into
active proliferation, thus increasing their susceptibility to cell cycle–
specific chemotherapeutic agents.

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 Treatment regimens and scheduling

Log kill phenomenon:

• Destruction of cancer cells by chemotherapeutic agents follows first-order
kinetics (that is, a given dose of drug destroys a constant fraction of cells).

• The term “log kill” is used to describe this phenomenon.

• For example, a diagnosis of leukemia is generally made when there are

about 109 (total) leukemic cells.

• Consequently, if treatment leads to a 99.999% kill, then 0.001% (10-5) of

109 cells (or 104 cells) would remain.

• This is defined as a 5-log kill.

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 Treatment regimens and scheduling

Log kill phenomenon:

• At this point, the patient will become asymptomatic, and the patient is in
remission.

• For most bacterial infections, a 5-log (100,000- fold) reduction in the

number of microorganisms results in a cure, because the immune system
can destroy the remaining bacterial cells.

• However, tumor cells are not as readily eliminated, and additional

treatment is required to totally eradicate the leukemic cell population.

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 Treatment regimens and scheduling

Pharmacologic shelters

• Leukemic or other tumor cells find shelters in tissues such as the CNS,

• Therefore, a patient may require irradiation of the craniospinal axis or

intrathecal administration of drugs.

• Similarly, drugs may be unable to penetrate certain areas of solid tumors

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 Combinations of drugs

• Combination drug chemotherapy is more successful than single-drug

treatment in most of the cancers for which chemotherapy is effective

• Cytotoxic agents in combination are with:

 Qualitatively different toxicities
 Different molecular sites
 Different mechanisms of action,

• Usually combined at full doses

• This results in higher response rates, due to additive and/or potentiated

cytotoxic effects, and nonoverlapping host toxicities

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 Combinations of drugs

• In contrast, agents with similar dose-limiting toxicities, such as

myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined
safely only by reducing the doses of each.

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 Advantages of drug combinations

1) Provide maximal cell killing within the range of tolerated toxicity

2) Effective against a broader range of cell lines in the heterogeneous tumor

population

3) Delay or prevent the development of resistant cell lines.

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Problems associated with chemotherapy

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 Resistance

• Some neoplastic cells (for example, melanoma) are inherently resistant to

most anticancer drugs.

• Other tumor types may acquire resistance to the cytotoxic effects of a

medication by mutating, particularly after prolonged administration of
suboptimal drug doses.

• The development of drug resistance is minimized by short-term, intensive,

intermittent therapy with combinations of drugs.

• Drug combinations are also effective against a broader range of resistant

cells in the tumor population

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 Multidrug resistance

• P-glycoprotein is responsible for multidrug resistance.

• This resistance is due to ATP– dependent pumping of drugs out of the cell.

• Cross-resistance following the use of structurally unrelated agents also

occurs.

• The presence of P-glycoprotein may account for the intrinsic resistance to

chemotherapy observed with adenocarcinomas.

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 Toxicity

• Therapy aimed at killing rapidly dividing cancer cells also affects normal
cells undergoing rapid proliferation. E.g. cells of :

 The buccal mucosa

 Bone marrow

 GIT mucosa

 Hair follicles

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 Common adverse effects

• Most chemotherapeutic agents have a narrow therapeutic index.

• They can cause:
 Severe vomiting
 Stomatitis
 Bone marrow suppression
 Alopecia

• Vomiting is often controlled by administration of antiemetic drugs.

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 Common adverse effects

• Some adverse reactions are confined to specific agents, such as:

 Bladder toxicity with cyclophosphamide
 Cardiotoxicity with doxorubicin,
 Pulmonary fibrosis with bleomycin.

• The duration of the side effects varies widely.

 Transient: Alopecia
 Irreversible: cardiac, pulmonary, and bladder toxicities

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 Minimizing adverse effects

Some toxic reactions may be ameliorated by interventions, such as:

• The use of cytoprotectant drugs

• Perfusing the tumor locally (for example, a sarcoma of the arm)

• Removing some of the patient’s marrow prior to intensive treatment and

then re-implanting it

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 Minimizing adverse effects

Some toxic reactions may be ameliorated by interventions, such as:

• Promoting intensive diuresis to prevent bladder toxicities.

• The megaloblastic anemia that occurs with methotrexate can be

effectively counteracted by administering folinic acid (leucovorin).

• With the availability of human “granulocyte colony–stimulating factor”

(filgrastim), the neutropenia associated with treatment of cancer by many
drugs can be partially reversed.

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 Problems associated with chemotherapy

Treatment-induced tumors:
• Because most antineoplastic agents are mutagens, neoplasms (for
example, acute nonlymphocytic leukemia) may arise 10 or more years
after the original cancer was cured.

• Treatment-induced neoplasms are especially a problem after therapy with

alkylating agents

• Most tumors that develop from cancer chemotherapeutic agents respond

well to treatment strategies

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Anticancer drugs

ANTIMETABOLITES

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 ANTIMETABOLITES

• Antimetabolites are structurally related to normal compounds that exist

within the cell.

• They generally interfere with the availability of normal purine or

pyrimidine nucleotide precursors, either by:
 Inhibiting their synthesis or
 Competing with them in DNA or RNA synthesis.

• Their maximal cytotoxic effects are in S-phase and are, therefore, cell cycle
specific.

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Methotrexate (MTX)

• MTX is structurally related to folic acid and acts

as an antagonist of the vitamin by inhibiting
mammalian dihydrofolate reductase.

• The inhibition of DHFR can only be reversed by:

 a 1000-fold excess of the natural substrate,
dihydrofolate (FH2), or

 by administration of leucovorin, which

bypasses the blocked enzyme and replenishes
the folate pool

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 ANTIMETABOLITES

• Leucovorin, or folinic acid, is the N5-formyl group–carrying form of FH4.

• MTX is specific for the S-phase of the cell cycle.

• Pemetrexed is an antimetabolite similar in mechanism to methotrexate.

• However, in addition to inhibiting DHFR, it also inhibits thymidylate

synthase and other enzymes involved in folate metabolism and DNA
synthesis.

• Pralatrexate is a newer antimetabolite that also inhibits DHFR

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 Therapeutic uses of MTX

MTX, usually in combination with other drugs, is effective against:

• Acute lymphocytic leukemia (ALL)

• Burkitt lymphoma in children

• Breast cancer

• Bladder cancer

• Head and neck carcinomas.

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 Therapeutic uses of MTX

Low-dose MTX is effective as a single agent against certain inflammatory

diseases as:
• Severe psoriasis

• Rheumatoid arthritis

• Crohn disease.

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 Pharmacokinetics of MTX

• MTX is administered orally, IM, IV, and intrathecally (does not penetrate
BBB).

• Distributes well to intestinal epithelium, liver, kidney, skin as well as in

ascites, pleural effusions.

• High doses results in crystalluria; avoid renal toxicity by keeping the urine
alkaline and the patient well hydrated.

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 Side effects of MTX

• N/V/D
• Stomatitis
• Rash
• Alopecia
• Myelosuppression
• High-dose: renal damage
• Intrathecal: neurologic toxicities

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 6-Mercaptopurine (6-MP)

• Thiol analog of hypoxanthine purine analog

Clinical use:
• Maintenance of remission in acute lymphoblastic leukemia.

• 6-MP and its analog, Azathioprine, can be used for Crohn disease

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 Mechanism of action of 6-MP

1. Nucleotide formation:
6-MP must penetrate target cells and be converted to the nucleotide
analog, 6-MP-ribose phosphate (TIMP).

2. Inhibition of purine synthesis: TIMP also blocks the formation of

adenosine monophosphate

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 Mechanism of action of 6-MP

3. Incorporation into nucleic acids:

 TIMP is converted to thioguanine monophosphate, which after
phosphorylation to di- and triphosphates can be incorporated into RNA.

 The deoxyribonucleotide analogs that are also formed are incorporated

into DNA.

 This results in nonfunctional RNA and DNA

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 Fludarabine

• Is a purine nucleotide analog.

• It is useful in the treatment of:

 Chronic lymphocytic leukemia (CLL)

 Hairy cell leukemia

 Indolent non-Hodgkin lymphoma

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 Mechanism of action Fludarabine

• Fludarabine is a prodrug,

• It is phosphorylated into triphosphate that is incorporated into both DNA

and RNA, decreases their synthesis in the S-phase

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 Cladribine

Mechansim of action of Cladribine

• Purine analog

• Undergoes reactions similar to those of Fludarabine

• It must be phosphorylated to a nucleotide to be cytotoxic.

• It becomes incorporated at the 3′-terminus of DNA and, thus, hinders

elongation.

• It also affects DNA repair and is a potent inhibitor of ribonucleotide

reductase.

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 Cladribine

• Spectrum of activity: similar to those of Fludarabine.

• Cladribine distributes throughout the body, including into the CSF.

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5-Fluorouracil (5-FU)

Clinical use of 5-FU: treatment of slowly growing

solid tumors, e.g.:
• Colorectal
• Breast
• Ovarian
• Pancreatic
• Gastric
• Topically, effective for the treatment of
superficial basal cell carcinomas.

5-FU = 5-fluorouracil
5-FUR = 5-fluorouridine
5-FUMP = 5-fluorouridine monophosphate
5-FUDP = 5-fluorouridine diphosphate
5-FUTP = 5-fluorouridine triphosphate
dUMP = deoxyuridine monophosphate
dTMP = deoxythymidine monophosphate 46
 Cytarabine

Mechanism of action:

• Acts as a pyrimidine antagonist.

• Must be phosphorylated to the nucleotide form (cytosine arabinoside

triphosphate or ara-CTP) to be cytotoxic.

• Ara-CTP is an effective inhibitor of DNA polymerase.

• The nucleotide is also incorporated into nuclear DNA and can terminate
chain elongation.

The major clinical use : in acute nonlymphocytic (myelogenous) leukemia (AML).

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Gemcitabine

• It is used most commonly for:

– Pancreatic cancer
– Non– small cell lung cancer

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Anticancer drugs

ANTIBIOTICS

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 Antibiotics

Their cytotoxic action is primarily due to:

• Their interactions with DNA, leading to disruption of DNA function.
• Their abilities to inhibit topoisomerases (I and II)
• Their ability to produce free radicals.

• All are cell cycle nonspecific except Bleomycin.

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 Anthracyclines

Common examples
• Doxorubicin
• Daunorubicin
• Idarubicin
• Epirubicin
• Mitoxantrone

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 Clinical uses of Anthracyclines

• Doxorubicin is used in combination with other agents for treatment of:

 Breast and lung cancers
 Acute lymphocytic leukemia and lymphomas.

• Daunorubicin and idarubicin: are used for Acute leukemias

• Mitoxantrone: is used in prostate cancer.

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 Mechanism of action of Anthracyclines

Produce free radicals that induce

• Membrane lipid peroxidation

• DNA strand scission

• Direct oxidation of purine/ pyrimidine

bases, thiols, and amines

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 Adverse effects of Anthracyclines

• Cardiotoxicity
 Irreversible and dose-dependent
 Caused by free radicals and lipid peroxidation (the most serious
adverse reaction)
 More common with Daunorubicin and Doxorubicin than with
Idarubicin and Epirubicin.

• Extravasation is a serious problem that can lead to tissue necrosis

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 Bleomycin

• Cause scission of DNA by an oxidative

process.

• It is cell cycle specific and causes cells

to accumulate in the G2 phase.

• Primary clinical use: Treatment of

testicular cancers and Hodgkin
lymphoma

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 Adverse effects of Bleomycin

• Pulmonary toxicity is the most serious adverse effect, progressing from

rales, cough, and infiltrate to potentially fatal fibrosis

• Mucocutaneous reactions (common)

• Alopecia (common)

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Anticancer drugs

ALKYLATING AGENTS

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 Alkylating agents

• Covalently bind to nucleophilic groups on various cell constituents.

• Alkylation of DNA is the crucial cytotoxic reaction that is lethal to the

tumor cells.

• Alkylating agents do not discriminate between cycling and resting cells,

• They are most toxic for rapidly dividing cells.

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 Alkylating agents

• They are used in combination with other agents to treat a wide variety of
lymphatic and solid cancers.

• All are mutagenic and carcinogenic and can lead to secondary

malignancies such as acute leukemia

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 Cyclophosphamide and Ifosfamide

• Used either singly or as part of a regimen

in the treatment of a wide variety of
neoplastic diseases, such as
 Non-Hodgkin lymphoma
 Sarcoma
 Breast cancer

• Cyclophosphamide can be given

orally or IV

• Ifosfamide is IV only

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 Adverse effects of Cyclophosphamide and Ifosfamide

• Hemorrhagic cystitis
 Can lead to fibrosis of the bladder.

 Due to the excretion of the toxic metabolite acrolein in the urine.

 Reduced by:
– Adequate hydration and
– IV injection of mesna (neutralizes acrolein)

• High incidence of neurotoxicity

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 Nitrosoureas

• Carmustine and Lomustine

• Can penetrate CNS, thus primarily employed in the treatment of brain

tumors

• More cytotoxic to dividing cells

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 Other alkylating agents

• Chlorambucil, Melphalan and Busulfan

• Used in lymphatic cancers

• Have moderate hematologic toxicities and upset the GI tract

• Busulfan can cause pulmonary fibrosis

• All of these agents are leukemogenic

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Anticancer drugs
MICROTUBULE INHIBITORS

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 Microtubules inhibitors

• The mitotic spindle is essential for the movements of structures occurring

in the cytoplasm of all eukaryotic cells.

• The mitotic spindle consists of chromatin plus a system of microtubules

composed of tubulin.

• The mitotic spindle is essential for the equal partitioning of DNA into the
two daughter cells that are formed when a eukaryotic cell divides.

• These drugs disrupt this process by affecting the equilibrium between the
polymerized and depolymerized forms of the tubulin, thereby causing
cytotoxicity

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 Vincristine (VX) and Vinblastine (VBL)

• Derived Vinca rosea plant (Vinca alkaloids)

• Structurally similar to one another, but their therapeutic indications are

different

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Mechanism of action of Vinca alkaloids

They are cell

cycle specific
and phase
specific

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 Clinical uses of Vincristine (VX)

• Acute lymphoblastic leukemia in children

• Wilms tumor

• Ewing soft tissue sarcoma

• Hodgkin and non-Hodgkin lymphomas

• Some other rapidly proliferating neoplasms

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 Clinical uses of Vinblastine (VBL)

• Metastatic testicular carcinoma: Administered with Bleomycin and

Cisplatin

• Systemic Hodgkin and non-Hodgkin lymphomas.

• Advanced non–small cell lung cancer: either as a single agent or with

Cisplatin

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 Adverse effects of Vinca alkaloids

• Both VX and VBL cause:

 Phlebitis or cellulitis, if the drugs extravasate during injection
 Nausea, vomiting & diarrhea
 Alopecia

• VBL is a more potent myelosuppressant than VX

• Peripheral neuropathy (paresthesias, loss of reflexes, foot drop, and

ataxia) is associated with VX

• Can be fatal if administered intrathecally

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 Paclitaxel and docetaxel

Microtubules stabilizers

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 Adverse effects of Paclitaxel and docetaxel

• Neutropenia and leukopenia.

• Alopecia

• Vomiting and Diarrhea (uncommon)

• Serious hypersensitivity reactions: Should premedicate patient with

Dexamethazone and Diphenhydramine

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Anticancer drugs
STEROID HORMONES AND THEIR ANTAGONISTS

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 Strategies for the treatment of steroid-sensitive tumors

Tumors that are steroid hormone sensitive may be either

1) Hormone responsive: the tumor regresses following treatment with a
specific hormone or

2) Hormone dependent: Removal of a hormonal stimulus causes tumor

regression; or

3) Both

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 Strategies for the treatment of steroid-sensitive tumors

Removal of hormonal stimuli from hormone-dependent tumors can be

accomplished :

• Surgically: e.g. orchiectomy or castration) or

• Pharmacologically: e.g. antiestrogens

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 Prednisone

• Potent, synthetic, anti-inflammatory corticosteroid with less

mineralocorticoid activity than cortisol

• At high doses, cortisol is lymphocytolytic and leads to hyperuricemia due

to the breakdown of lymphocytes

• Prednisone is a prodrug that is bioactivated into Prednisolone by the liver

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 Prednisone

Prednisone is primarily employed to induce remission of:

• Acute lymphocytic leukemia (ALL)
• Hodgkin lymphomas
• non-Hodgkin lymphomas

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 Tamoxifen

• It is classified as a selective estrogen receptor modulator (SERM)

• It is an estrogen antagonist with some estrogenic activity

• first-line therapy in the treatment of estrogen receptor–positive breast

cancer

• Used prophylactically in reducing breast cancer occurrence in women who

are at high risk.

• Can stimulate premalignant lesions due to its estrogenic properties:

patients should be closely monitored during therapy.

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Mechanism of action of Tamoxifen

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 Mechanism of action of Tamoxifen

• Binds to estrogen receptors in the breast tissue, but the complex is unable
to translocate into the nucleus for its action

• The result is a depletion (down-regulation) of estrogen receptors

• Estrogen competes with Tamoxifen. Therefore, in premenopausal women,

the drug is used with a gonadotropin releasing hormone (GnRH) analog
such as Leuprolide, which lowers estrogen levels.

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 Adverse effects of Tamoxifen

• Hot flashes

• Nausea & vomiting

• Vaginal bleeding & discharge (due to estrogenic activity of the drug and
some of its metabolites).

• Hypercalcemia

• Increased pain if the tumor has metastasized to bone

• Thromboembolism

• May cause endometrial cancer

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 Raloxifene

• It is a SERM given orally that acts to block estrogen effects in the uterine
and breast tissues, while promoting effects in the bone to inhibit
resorption.

• Reduce the risk of estrogen receptor– positive invasive breast cancer in

postmenopausal women

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 Fulvestrant

• An estrogen receptor antagonist

• Given to patients with hormone receptor– positive metastatic breast

cancer.

• Binds to and causes estrogen receptor down-regulation on tumors and

other targets

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 Aromatase inhibitors

• Anastrozole and Letrozole

• The aromatase reaction is responsible for the extra-adrenal synthesis of

estrogen, which takes place in:
 liver, fat, muscle, skin, and breast tissues, including breast
malignancies

• Peripheral aromatization is an important source of estrogen in

postmenopausal women.

• Aromatase inhibitors decrease the production of estrogen in these women

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 Anastrozole and letrozole

• Nonsteroidal aromatase inhibitors.

• They do not predispose patients to endometrial cancer

• They are devoid of the androgenic side effects

• in the United States they are considered second-line therapy after

Tamoxifen for hormone dependent breast cancer

• They have become first-line drugs in other countries for the treatment of
breast cancer in postmenopausal women.

• They are orally active and cause almost a total suppression of estrogen
synthesis

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Aromatase inhibitors & Tamoxifen for Breast cancer therapy

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 Progestins

• Megestrol used in treating metastatic hormone-responsive breast and

endometrial neoplasms

• Aromatase inhibitors are replacing it in therapy

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 Leuprolide, Goserelin, and Triptorelin

• Synthetic analogs of GnRH

• Continuous administration leads to receptor desensitization and,

consequently, inhibition of FSH and LH release

• LH stimulus for the secretion of testosterone by the testes

• FSH stimulates the secretion of estrogen

• These drugs reduce both androgen and estrogen syntheses

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 Leuprolide, Goserelin, and Triptorelin

• Response to Leuprolide in prostatic cancer is equivalent to that of

orchiectomy with regression of tumor and relief of bone pain

• They are beneficial for women with advanced breast cancer and have
largely replaced estrogens in therapy for prostate cancer

• They are available as:

 Sustained-release intradermal implant
 Subcutaneous depot injection
 Intramuscular depot injection

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 Adverse effects of GnRH analogues

• Impotence

• Hot flashes

• Tumor flare

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 Estrogens

• Example: Ethinyl estradiol

• Used in the treatment of prostatic cancer.

• They have been largely replaced by the GnRH analogs because of fewer
adverse effects.

• Estrogens inhibit the growth of prostatic tissue by blocking the production

of LH, thereby decreasing the synthesis of androgens in the testis

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 Side effects of Estrogens

• Thromboemboli

• Myocardial infarction

• Strokes

• Hypercalcemia

• Men who are taking estrogens may experience gynecomastia and

impotence

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 Nonsteroidal antiandrogens

• Flutamide, Nilutamide, and Bicalutamide

• They compete with the natural hormone for binding to the androgen
receptor and prevent its translocation into the nucleus

• Used in the treatment of prostate cancer

• Side effects:
 Gynecomastia
 GI distress
 Liver failure (Rare)

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Anticancer drugs
MONOCLONAL ANTIBODIES

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 Trastuzumab

• Used for metastatic breast cancer, overexpressing transmembrane

“human epidermal growth factor receptor protein 2” (HER2)

• HER2 is overexpressed in 25% to 30% of patients with breast cancer

• HER2 can be also expressed in gastric and gastroesophageal cancers

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 Mechanism of action of Trastuzumab

• Binds to HER2 receptors and inhibits cell proliferation

• It blocks downstream signaling pathways

• It induces antibody-dependent cytotoxicity

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 Adverse effects of Trastuzumab

• Congestive heart failure

• Cardiotoxicity is worsened if given in combination with anthracyclines

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 Rituximab

• Directed against the CD20 antigen that is found on the surfaces of normal
and malignant B lymphocytes

• CD20 antigen is expressed on nearly all B-cell non-Hodgkin lymphomas but

not in other bone marrow cells

• CD20 plays a role in the activation process for cell cycle initiation and
differentiation

98
 Mechanism of action of Rituximab

• Upon binding to CD20, the Fc domain of the antibody induces

complement and antibody-dependent, cell-mediated cytotoxicity against B
cells

• Rituximab is effective in the treatment of:

 Lymphomas
 Chronic lymphocytic leukemia
 Rheumatoid arthritis

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 Adverse effects of Rituximab

• Severe fatal hypersensitivity reactions, especially in patients with high

circulating levels of neoplastic cells

• Occurs due to rapid activation of complement which results in the release

of tumor necrosis factor-α (TNF-α) and interleukins

• Pretreatment with diphenhydramine, acetaminophen, and corticosteroids

can ameliorate these problems

100
 Adverse effects of Rituximab

• Tumor lysis syndrome: Occurs within 24 hours of the first dose of

Rituximab. Consists of:

 Hyperkalemia
 Hypocalcemia
 Hyperuricemia
 Hyperphosphatasemia
 Acute renal failure that may require dialysis.

101
 Bevacizumab

• An IV antiangiogenesis agent.

• Directed against vascular endothelial growth factor (VEGF)

• Stops VEGF from stimulating the formation of new blood vessels

(neovascularization).

• Without new blood vessels, tumors do not receive the oxygen and
essential nutrients necessary for growth and proliferation.

102
 Clinical uses of Bevacizumab

• Approved for use as a first-line drug against metastatic colorectal cancer in

combination with 5-FU–based chemotherapy.

• Diabetic retinopathy (intravitreous injection)

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 Cetuximab

• Targets the epidermal growth factor receptor (EGFR) on the surface of

cancer cells and interfering with their growth

• Approved to treat KRAS wild-type metastatic colorectal cancer and head

and neck cancers

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Anticancer drugs
PLATINUM COORDINATION COMPLEXES

105
 Drugs

• Cisplatin

• Carboplatin

• Oxaliplatin

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 Mechanism of action

• Bind to guanine in DNA, forming inter- and intrastrand crosslinks.

• The resulting cytotoxic lesion inhibits both polymerases for DNA

replication and RNA synthesis.

• Cytotoxicity can occur at any stage of the cell cycle, but cells are most
vulnerable to the actions of these drugs in the G1 and S-phases.

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 Clinical use

• Metastatic testicular carcinoma in combination with VBL and bleomycin

• Ovarian carcinoma in combination with cyclophosphamide

• Bladder carcinoma: alone

• Oxaliplatin is used in the setting of colorectal cancer.

108
 Adverse effects

• Severe, persistent vomiting occurs for at least 1 hour after administration

of Cisplatin and may continue for as long as 5 days.
 Premedication with antiemetic agents is required.

• The major limiting toxicity of Cisplatin is dose-related nephrotoxicity

 Can be prevented by aggressive hydration.

• Ototoxicity with high-frequency hearing loss and tinnitus.

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 Adverse effects

• Unlike Cisplatin, Carboplatin causes only mild nausea and vomiting, and it
is rarely nephro-, neuro-, or ototoxic

• Myelosuppression

• Hepatotoxicity

• Anaphylaxis

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Anticancer drugs
TOPOISOMERASE INHIBITORS

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 Topoisomerase inhibitors

• They inhibit topoisomerase enzymes that reduce supercoiling of DNA

Drugs

• Camptothecins
 Irinotecan and Topotecan
 They are plant semisynthetic alkaloids of Camptotheca tree

• Etoposide
 Semisynthetic derivative of the plant alkaloid, podophyllotoxin

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Mechanism of action of Camptothecins

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 Camptothecins

• Topotecan is used in
 metastatic ovarian cancer when primary therapy has failed
 treatment of small cell lung cancer.

• Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal
carcinoma.

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 Etoposide

Mechanism of action

• The drug binds the enzyme-DNA complex

• This results in persistence of the transient cleavable form of the complex

and causes irreversible double-strand breaks.

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Mechanism of action of Etoposide

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 Etoposide

• Clinical use:
 Treatment of lung cancer
 Testicular carcinoma: in combination with bleomycin and cisplatin.

• Major toxicity: Dose-limiting myelosuppression (primarily leukopenia)

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Anticancer drugs
TYROSINE KINASE INHIBITORS

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 Imatinib

• A deregulated BCR-ABL kinase is present in the leukemia cells of almost

every patient with CML and GI stromal tumors

• BCR-ABL kinase is associated with cell proliferation

• Imatinib is designed to inhibit this mutated enzyme

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 Erlotinib

• an inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase.

• Approved for the treatment of non–small cell lung cancer and pancreatic
cancer

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Anticancer drugs
MISCELLANEOUS AGENTS

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 Procarbazine

• Inhibits DNA, RNA, and protein synthesis

• Distributes rapidly to the CNS

Side effects:
• Bone marrow depression (major toxicity)

• Nausea, vomiting, and diarrhea (common)

• Neurotoxicity: drowsiness, hallucinations and paresthesias

• Mutagenic and teratogenic: Nonlymphocytic leukemia has developed in
patients treated with the drug.
• It inhibits MAO: avoid with foods containing tyramine

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 Asparaginase

• Some neoplastic cells require an external source of asparagine because of

limited capacity to synthesize sufficient amounts of the amino acid to
support growth and function

• Asparaginase catalyzes the deamination of asparagine to aspartic acid and

ammonia, thus depriving the tumor cells of this amino acid, which is
needed for protein synthesis

• Clinical use: treatment of childhood acute lymphocytic leukemia in

combination with VX and prednisone

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 Interferons

• α-interferons: produced by leukocytes

• β- interferons: produced by connective tissue fibroblasts

• γ- interferons: produced by T lymphocytes

• interferon-α-2a and 2b: are produced by Recombinant DNA techniques

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 Interferons

• Interferon-α-2a is approved for the management of hairy cell leukemia,

CML, and AIDS-related Kaposi sarcoma

• Interferon-α-2b is approved for the treatment of hairy cell leukemia,

melanoma, AIDS-related Kaposi sarcoma, and follicular lymphoma

• the exact mechanism by which the interferons are cytotoxic is unknown.

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