Download Anti-neoplastic Drugs

DEPARTMENT OF PHARMACEUTICS
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Cancer
• In most cases, causes of cancer is
multifactorial (environmental, genetic)
• 25% of population of U.S will be diagnosed with
cancer during their lifetime
• Cancer is ranked as a second cause of mortality
after cardiovascular diseases
• Overall five-year survival rate for cancer
patients is about 40%
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Characteristics of cancer cells
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Growth that is not subject to normal restrictions
Local invasiveness
Spread to other part of body (metastasis)
Less differentiated cell morphology
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Therapeutic methods to treat Cancer
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Surgery
Radiotherapy
Chemotherapy
Endocrine therapy
Immunotherapy
Biological therapy
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Principles of cancer chemotherapy (CC)
• Cytotoxic chemotherapy exert their effects
by inhibiting cell proliferation
• They interfere with cell division at various
points of cell cycle
• Anticancer drugs affect all proliferating cells
both normal & abnormal cells
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Principles of cancer chemotherapy
• They attack metabolic sites essential to cell
replication e.g. purines & pyrimidines
synthesis that are building blocks for DNA &
RNA synthesis
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Goal of treatment
- A cure (disease-free survival) that requires
eradication of neoplastic cells
- Palliation (Alleviation of symptoms &
avoidance of life-threatening toxicity)
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Indications for treatment
When neoplasms are disseminated & not
amenable to surgery
Adjuvant therapy following surgery &
radiation therapy
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Tumor susceptibility & growth cycle
Both normal & tumor cells go through growth
cycles
They differ number of cells in each stage
Rapidly dividing cells are more sensitive to
anticancer drugs
Nonproliferating cells (those in G0) survive
toxic effect of drugs
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1. Cell cycle specific drugs
Effective only against replicating cells (highgrowth-fraction malignancies e.g. hematologic
cancers)
Antimetabolites, antibiotics, vinca alkaloids,
Etoposide
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2. Cell-cycle non-specific drugs
- Effective for both low-fraction malignancies e.g.
solid tumors as well as high growth fraction
malignancies
- Alkylating agents, Cisplatin, nitrosoureas
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Effects of chemotherapeutic agents on growth
cycle
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Combinations of Drugs
• Combination-drug chemotherapy is more
successful than single-drug treatment
• Cytotoxic agents with different toxicities,
molecular sites & mechanisms of action are
usually combined
• This results in higher response rate & nonoverlaping host toxicities
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Advantages of drug combinations
Provide maximal cell killing within range of
tolerated toxicity
Are effective against broader range of cell
lines
May delay or prevent development of
resistant cell lines
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Treatment protocols
• Many cancer treatment protocols have been
developed
• A common regimen called POMP used for
treatment of acute lymphocytic leukemia (ALL)
consists of Prednisone, Oncovin (vincristine),
Methotrexate & Purinethol (mercaptopurine)
• Therapy is scheduled intermittently to allow
recovery of normal tissue
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Problems associated with chemotherapy
1. Resistance
2. Multidrug resistance
3. Toxicity
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1. Resistance
Some neoplastic cells inherent resistance to
anticancer drugs e.g. melanoma
Others acquired resistance after prolonged
administration of low drug doses
Drug resistance is minimized by short-term,
intensive, intermittent therapy with
combinations of drugs
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2. Multidrug resistance
• MDR gene that codes for a transmembrane
protein (P-glycoprotein) is responsible for
multidrug resistance
• Resistance is due to ATP-dependent pumping
of drugs out of cell
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2. Multidrug resistance
• The six membranespanning loops of Pglycoprotein form a
central channel for ATPdependent pumping of
drugs from cell
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3. Toxicity
Therapy aimed at killing rapidly dividing
abnormal cells
It also affects normal cells undergoing rapid
proliferation e.g. cells of buccal mucosa, bone
marrow, GI mucosa & hair folicle, contributing
to toxic manifestation of chemotherapy
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Common adverse effects
Severe vomiting
Stomatitis
Alopecia
Myelosuppression
Opportunistic infections (gram –ve)
Cardiotoxicity with doxorubicin
Pulmonary fibrosis with bleomycin
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Minimizing adverse effects
• Perfusion tumor locally (sarcoma of arm)
• Removing patient’s marrow prior to intensive
treatment & then reimplanting it
• Promoting intensive diuresis to prevent bladder
toxicity
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Minimizing adverse effects
• Administration of folinic acid (methotrexateinduced megaloblastic anemia)
• Filgrastim (neupogen) (human granulocyte
colony-stimulating factor G-CSF) to counteract
neutropenia
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Anticancer drugs
1. Antimetabolites
2. Antibiotics
3. Alkylating agents
4. Microtubule inhibitors
5. Steroid hormones & their antagonists
6. Monoclonal antibodies
7. Others
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