Anti-Cancer

Anti- cancer drugs

Overview
 It is estimated that over 25% of population of United States will face a
diagnosis of cancer during their lifetime, with more than 1.6 million new
cancer patients diagnosed each year.
 There are three approaches to treating established cancer:
1) Surgical excision
2) Irradiation
3) Drug therapy
 The value of each approach depends on :
1) The disease
2) The stage of its development.

Principles Of Cancer Chemotherapy

 Cancer chemotherapy strives to cause 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, for example, the availability of purines and
pyrimidines, which are the building blocks for DNA or RNA synthesis.
 Ideally, these anticancer drugs should interfere only with cellular processes
that are unique to malignant cells.
 Unfortunately, most currently available anticancer drugs do not specifically
recognize neoplastic cells but, rather, affect all kinds of proliferating cells,
both normal and abnormal, therefore almost all antitumor agents have a steep
dose–response curve for both therapeutic and toxic effects.

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Goals of chemotherapy: (cure, control or palliative)
1) The ultimate goal of chemotherapy is a cure
 True cure requires the eradication of every neoplastic cell.
2) 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.
3) Relieve symptoms caused by the cancer and improve the quality of
life
 Even though the drugs may not extend survival.

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

influences treatment decisions.

Indications of chemotherapy:
 Chemotherapy is sometimes used when neoplasms are disseminated and are
not amenable to surgery
 Chemotherapy used as a supplemental treatment to attack
Adjuvant
micro-metastases following surgery and radiation
chemotherapy
treatment
Neoadjuvant  Prior to the surgical procedure in an attempt to shrink the
chemotherapy cancer
Maintenance  In lower doses to assist in prolonging a remission
chemotherapy

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 Anticancer drugs

Classification :
I. Cytotoxic drugs:
 Alkylating agents
 Anti-metabolites
 Antitumor antibiotics
 Plant derivatives
II. Hormones.
III. Monoclonal antibodies.
V. Miscellaneous agents.
I. Cytotoxic drugs:
A) Alkylating agents

 Nitrogen mustard: cyclophosphamide.

Groups  Platinum compounds: cisplatin.

 Nitrosoureas: carmustine
 They form reactive molecular species that alkylate DNA bases.

Mechanism  This leads to cross-linking of alkylated bases and DNA strand

breakage.

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 B) 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 :
Definition
a) inhibiting their synthesis
b) competing with them in DNA or RNA synthesis.
 Their maximal cytotoxic effects are in S-phase and are,
therefore, cell cycle specific.
1) Folate antagonists: Methotrexate :
 Inhibits dihydrofolate reductase (DHFR), preventing
generation of folinic acid (active form) from folic acid
2) Pyrimidine analogues: 5-fluorouracil :
Groups
 Converted to 5-fluorodeoxyuridine monophosphate
(5FdUMP).
3) Purine analogues: 6-Mercaptopurine (6MP) :
 Converted to 6-thioinosinic acid or TIMP

Mechanism  Blocking the synthesis of DNA and/or RNA

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 C) Antitumor antibiotics

 Bleomycin.
Groups
 Anthracyclines: Doxorubicin
 They generates free radicals which bind to DNA & cause :

Mechanism a) Strand breaks .

b) Inhibit DNA synthesis.

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 D) Plant derivatives

 Vinca alkaloids eg Vincristine.

 Taxanes e.g. Paclitaxel

Groups

 They block the formation of the mitotic spindles.

Mechanism  Their maximal cytotoxic effects are in M-phase and are,

therefore, cell cycle specific

This slide just for explanation

❑ The mitotic spindle is part of a larger, IC skeleton(cytoskeleton) that is
essential for movements of structures occurring in the cytoplasm of all
eukaryotic cells.
❑ It is essential for the equal partitioning of DNA into the two daughter cells.

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❖ Classifications of cytotoxic` drugs According to their effect on the cell cycle:
 Some drugs act at all phases of the cell cycle
 Others exert effects specifically at certain phase.

Cell cycle nonspecific (CCNS) Cell cycle specific (CCS)

❑ kill resting as well as dividing cells ❑ e.g.
 Cyclophosphamide  S phase: 5-fluorouracil, MTX
 Cisplatin  M phase: Vincristine, Paclitaxil

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 II. Hormones

Hormones or their antagonists are used in hormone-sensitive tumors e.g.:

Glucocorticoids Antiestrogen Antiandrogens
 For leukaemia and  For breast cancer  For prostatic cancer
lymphomas

Antiestrogen

 Selective Estrogen Receptor Modulator (SERM) (an estrogen

antagonist with some estrogenic activity)
 It blocks the binding of estrogen to receptors of estrogen-

sensitive cancer cells in breast tissue  Not pure antagonist

 Used in the treatment of advanced, estrogen receptor +ve

A. Tamoxifen breast cancer.

Side effects :
 include hot flashes, nausea, vomiting, skin rash, and vaginal
bleeding (due to estrogenic activity of the drug )
 increases the risk of hyperplasia and neoplasia (agonist
activity in the endometrium
 an estrogen receptor antagonist
 given via IM injection to patients with hormone receptor +ve

B. Fulvestrant metastatic breast cancer.

 This agent binds to and causes estrogen receptor down-
regulation

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 III. Monoclonal antibodies:

 Many tumors overexpress growth factor receptors that stimulate cell

proliferation & growth.
 This can be inhibited by monoclonal antibodies.
 Monoclonal antibodies are directed at specific targets and often have
fewer adverse effects.

❑ Human epidermal growth factor receptor protein 2 (HER2)

is overexpressed in :
1) Breast cancer ( 25% to 30% of patients).
A. Trastuzumab 2) Gastric
3) Gastroesophageal cancers.
❑ Trastuzumab binds to HER2 sites and inhibits proliferation
of cells .
❑ First monoclonal antibody to be approved for the treatment
of cancer (prototype ).
B. Rituximab
❑ Directed against the CD20 antigen that is found on the
surfaces of normal and malignant B lymphocytes.
❑ Epidermal growth factor receptor (EGFR) is a member of
erb-B family of growth factor
❑ it is overexpressed in several tumors, including colorectal
cancer.
❑ Cetuximab is monoclonal antibody directed against the
C. Cetuximab
extracellular domain of the EGFR
❑ it is presently approved for use in combination with
irinotecan for metastatic colon cancer

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 ❑ Vascular endothelial growth factor (VEGF) is one of the most
important angiogenic growth factors
❑ Bevacizumab is a monoclonal antibody that targets all forms
of VEGF-A.
D. Bevacizumab ❑ This antibody binds to and prevents VEGF-A from interacting
with the target VEGF receptors.
❑ Bevacizumab can be safely and effectively combined with
5-FU or irinotecan-based chemotherapy in the treatment of
metastatic colorectal cancer.

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 Problems and precautions associated with chemotherapy

1. Resistance:
 Some neoplastic cells are inherently resistant to most anticancer drugs.
 Other tumor types may acquire resistance to the cytotoxic effects of drugs
by mutating, particularly after prolonged administration of suboptimal
drug doses.
2. Multidrug resistance:
 Due to ATP pumping of drugs out of the cell in presence of P-glycoprotein.

3: Toxicity:
 Therapy aimed at killing rapidly dividing cancer cells also affects normal
cells undergoing rapid proliferation (for example, cells of the buccal
mucosa, bone marrow, gastrointestinal mucosa, and hair follicles), contributing
to the toxic manifestations of chemotherapy.
 These can be divided into:
General adverse effects Specific adverse effects
 Nausea and vomiting  Cyclophosphamide: Hemorrhagic Cystitis.
 Diarrhea and malabsorption  Cisplatinum: Nephrotoxicity
 Bone marrow toxicity
 Methotrexate: Marrow suppression,
(myelosuppression)
Macrocytic anemia
 Opportunistic infections
 Fluorouracil: Marrow suppression.
 Loss of hair (Alopecia)
 Depression of growth in  Doxorubicin: Cardiotoxicity
children (cardiomyopathy) and arrhythmias
 Sterility  Bleomycin: Pulmonary fibrosis
 Teratogenicity  Vincristine: Peripheral neuropathy

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4: Drug combination:
 Combination drug chemotherapy is more successful than single-drug
treatment.
 Advantages of drug combinations:
1) Maximal cell killing within the range of tolerated toxicity.
2) Effective against a broader range of cell lines
3) Delay or prevent the development of resistance .

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