Anticancer Drugs
Dr.Qamar Barakzai
Department of Pharmacology
Ziauddin Medical University
Karachi.Pakistan
“CANCER”
Refers to a Malignant neoplasm (New growth)
Cancer cells can manifest:
•
•
•
•
Uncontrolled Proliferation.
Loss of function due to lack of ability to differentiate.
Invasiveness.
The ability to metastasize.
Cancer arises as a result of a series of genetic changes
in the cell, the main genetic lesions being:
• Inactivation of tumor suppressor genes.
• The activation of oncogenes.
Antineoplastic agents
•
•
•
Are cytotoxic not tumoricidal
Only kill cells during mitosis, and
Not all cancer cells are dividing at the same time.
SUCCESS DEPENDS ON:
• Stage of cancer at time of diagnosis
• Type of cancer
• Development of drug resistance
• Overall health of patient.
M
G2
S PHASE
SPECIFIC
Cytosine
Arbinoside
Hydroxyurea
DNA
S PHASE
SPECIFIC
Synthesis
SELF LIMITING
6-Mercaptpurine
Methotrexate.
Premitotic
Interval
S
M
PHASE
PROPHASE
METAPHASE
SPECIFIC
ANAPHASE
vincristine
TELOPHASE
vinblastine
paclitaxel
MITOSIS
PHASE NONSPECIFIC
• Tumor
Suppressor
alkylating
agents, cis-platinum
Genes -ve (p53)
nitrosoureas,
dacarbazine
• Growth
Factors
antibiotics
R
Oncogenes
+ve
procarbazine
G1
G0
Differentiation
G0
CELL GROWTH CYCLE
5 DISTINCT PHASES OF MITOSIS
1.
2.
3.
4.
5.
G0 G1 S G2 M-
Resting - no mitosis
Postmitotic - first growth
DNA synthesis phase
Premitotic - second growth
Mitosis phase
GENERATION TIME - one complete cycle different
in all tumors, from hours to days
ANTINEOPLASTIC
DRUGS
ALKYLATING
AGENTS
ANTIMETABOLITES
NATURAL
PRODUCTS
HORMONES AND
ANTAGONISTS
MISCELLANEOUS AGENTS
PENTOSTATIN
Pyrimidine
synthesis
Purine
synthesis
Inhibits adenosine
Deaminase
PALA
Inhibits Pyrimidine
Biosynthesis
Ribonucleotides
6-MERCAPTOPURINE
6-THIOGAUNINE
Inhibit Puring ring
biosynthesis
Inhibit Neocleotide
interconversions
HYDROXYUREA
Deoxyribonucleotides
METHOTREXATE
Inhibit dihydrofolate
reduction, blocks
TMP and Purine
synthesis
Inhibit
Ribonucleotide
Reductase
5-FLOUROURACIL
Inhibit TMP
Synthesis
DNA
BLEOMYCIN
ETOPOSIDE
TENIPOSIDE
DNA
Damage DNA and
Prevent repair
DACTINOMYCINE
DAUNORUBICIN
DOXORUBICIN
MITOXANTRONE
Intercalate with DNA
Inhibit RNA synthesis
A-ASPARAGINASE
Deaminate
asparagine
Inhibits protein
synthesis
CYTARABINE
FLUDARABINE
2-CHLORODEOXY
ADENOSINE
Inhibit DNA
Synthesis
RNA
ALKYLATING AGENTS
MITOMYCETIN
CISPLATIN
PROCARBAZINE
DACARBAZINE
(Transfer, messenger, ribosomal)
Form adducts w/ DNA
PROTEINS
PACLITAXEL
VINCA ALKALOIDS
COLCHICINE
Enzymes
Microtubules
Inhibit function of
Microtubules
ANTINEOPLASTIC AGENTS
DEFINITIONS:
•  ALKYLATION - chemical reaction that cleaves DNA and
interferes with mitosis
•  BIFUNCTIONAL ALKYLATING AGENTS - have 2 alkyl groups
and alkalate 2 DNA strands
•  DOSE-LIMITED SIDE EFFECTS - adverse effects that prevent
an agent from being given in higher doses
•  EMETIC POTENTIAL - potential of an agent to cause N & V
ANTINEOPLASTIC AGENTS
ADVERSE EFFECTS:
•
•
•
•
Kills all fast growing cells
Hair follicles
GI tract mucosa
Bone marrow suppression (BMS)
causing anemiaand leukopenia
• All are pregnancy category D !
• Most are nephro- hepato- and ototoxic
• Extravasation of IV can result in loss of limb
Antineoplastic Agents
ADVERSE EFFECTS: (Contd)
•
•
•
•
All have a BMS and emetic index
All have wide interaction with other drugs.
Special training required for nursing
Most agents can be harmful to nurse administering them
DEFINITIONS:
• GROWTH FRACTION
% of cells in mitosis at any given time
• LEUCOVORIN RESCUE use of leucovorin to reverse methotrexate-induced toxicity
• MITOTIC INDEX
number of cells per unit undergoing mitosis during a given time
• NADIR
lowest point (as in blood count) after being depressed by chemotherapy
• PARANEOPLASTIC SYNDROME (PNS)
S/S of cancer located distant from tumor or its metastatic sites
ANTINEOPLASTIC AGENTS
2 MAIN GROUPS OF AGENTS:
CELL CYCLE - NONSPECIFIC (CCNS)
ALKYLATING AGENTS
cytotoxic in any phase of cell cycle
effective against slowly growing tumors
CELL CYCLE - SPECIFIC (CCS) 3 TYPES
ANTIMETABOLITES - cytotoxic is S phase
MITOTIC INHIBITORS - cytotoxic in M phase
CYTOTOXIC ANTIBIOTICS (some are CCNS)
effective against rapidly growing tumors
ALKYLATING AGENTS
NITROGEN MUSTARDS
first developed in 1940s
CCNS killing ability
mechlorethamine is the prototypical agent
USES: Hodgkin’s disease & lymphomas.
leukemias,
CANCERS OF
lung,
breast,
ovary,
testes,
brain,
bladder,
Most widely used agent, often in combination with other agents.
ALKYLATING AGENTS
SELECTED AGENTS:
•Mechlorethamine (Mustine, Mustargen)
IV only (adult use only)
•Cyclophosphamide (Cytoxan, Neosar)
IV and PO, adults and pediatric use
•Carmustine (BiCNU)
IV, adult only, can cross blood-brain barrier,
therefore used to tread brain lesions
OTHER AGENTS: Chlorambucil, Streptozotocin
Hepatic cytochrome
P450 0xidase
Cyclophosphamide (Inactive)
4-Hydroxycyclophosphamide
Aldophosphamide
Enzymatic
Non enzymatic
Hepatic aldehyde oxidase
4-Ketocyclophosphamide
(Inactive).
Acrolein Cytotoxic
Phosphamide Mustard
Cytotoxic.
Carboxyphosphamide (Inactive).
Responsible for unwanted effects
Cyclophosphamide (Inactive)
Hepatic cytochrome
P450 0xidase
Aldophosphamide
4-Hydroxycyclophosphamide
Enzymatic
Hepatic aldehyde oxidase
Non enzymatic
4-Ketocyclophosphamide
(Inactive).
Acrolein Cytotoxic
Phosphamide Mustard
Cytotoxic
Carboxyphosphamide (Inactive).
Responsible for unwanted effects
ANTIMETABOLITES
ACTIONS:
•Antagonism of folate,
•purines, and pyrimidines needed for synthesis of nucleic acids •stops cell replication
USES:
•Solid tumors
(breast, lung, liver, brain, colon. Stomach, pancreas)
•Lymphomas, leukemias.
•Some agents also immunosuppressive,
•Useful in treating immune-mediated diseases
ANTIMETABOLITES
SELECTED AGENTS: (FOLIC ACID ANALOG)
• METHOTREXATE (Folex, Rheumatrex, MTx)
• Folic acid antagonist
•
PO & IM, adult and pediatric use
• Also used to treat immune-mediated diseases,
• Used incombination with misoprostol for therapeutic abortion
• Causes profound anemia (folate depletion)
• Therefore leucovorin “rescue” often used to counteract
ANTIMETABOLITES
SELECTED AGENTS:
• PURINE ANALOG
- MERCAPTOPURINE (6-MP, Purinethol)
- Purine antagonist
- PO only, adult and pediatric use
• PYRIMIDINE ANALOG
•CYTARABINE (Ara-C, Cytosar-U)
-Pyrimidine antagonist
-IV and intrathecal (within spinal canal)
MITOTIC INHIBITORS
ACTIONS:
Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.)
Bind to and disrupt mitotic spindles
USES:
Lymphomas (Hodgkin’s and non-Hodgkin’s),
Neuroblastoma
Kaposi’s sarcoma,
Solid tumors (breast, testicular, etc.)
MITOTIC INHIBITORS
SELECTED AGENTS:
ETOPOSIDE (VP-16, VePesid)
IV and PO, adult use only
PACLITAZEL (Taxol)
IV only, adult use only
drug of choice for ovary and breast ca
VINCRISTINE (LCR, VCR,Oncovin)
IV only, adult and pediatric use
drug of choice for acute leukemia
CYTOTOXIC ANTIBIOTICS
ACTIONS:
• Source: Streptomyces mold - work by intercalation (insertion of
drug molecule between the 2 DNA strands causing it to (“unwind”)
• Kill some bacteria and viruses but are too toxic to use for
infections
IV extravasation constant danger !
USES:
wide variety of solid tumors,
always used in combination with other agents
CYTOTOXIC ANTIBIOTICS
SELECTED AGENTS:
DOXORUBICIN (ADR, Rubex, Doxil)
IV only, adult use only
BLEOMYCIN (BLM, Blenoxane)
IM, IV, SQ, adult use only
very toxic agents !!!
MISCELLANEOUS ANTINEOPLASTICS
Various actions,
Both CCNS and CCS
Used in combinations with other agents
SELECTED AGENTS:
•Cisplatin (Platinol)
IV, adult and pediatric use
•ALTRETAMINE (Hexalen)
•
PO only, adult use only, primarily used to treat ovarian cancer
•ASPARAGINASE (Elspar)
•
IV only, adult and pediatric use
•HYDROXYUREA (Hydrea)
PO only, adult use only
MISCELLANEOUS ANTINEOPLASTICS
HORMONES AND ANTAGONISTS.
1. Adrenocortical Suppressant:
Mitotane, Aminoglutethimide. (Adrenal Cortex)
2.Adrenocortical Steroids.
Prednisone. (Lukemias, Lymphomas, Breast)
3.Progestins.
Hydroxyprogestrone.(Endometrium, (Breast)
Medroprogestrone, Megesterol acetate.
4.Estrogens.
DES, Ethinylesterdiol.(Breast, Prostate)
5.Antiestrogens.
Tamoxifen .(Breast)
6.Androgens.
Testosterone (Breast)
7.Antiandrogens.
Flutamide (Prostate).
8.Gonadotropin Releasing Hormone Analog.
Leuprolide. (Prostate)