Characteristics of Cancer Cells
• The problem:
– Cancer cells divide rapidly (cell cycle is
– They are “immortal”
– Cell-cell communication is altered
– uncontrolled proliferation
– Ability to metastasise
• After completion of mitosis, the resulting
daughter cells have two options:
• (1) they can either enter G1 & repeat the cycle or
• (2) they can go into G0 and not participate in the cell
• The ratio of proliferating cells to cells in G0, is called
the growth fraction.
• A tissue with a large percentage of proliferating cells
& few cells in G0 has a high growth fraction.
• Conversely, a tissue composed of mostly of cells in G0
has a low growth fraction.
• Cell Cycle Specific Drugs:
• Bleomycin peptide antibiotics
• Vinca alkaloids
Effective for high
• Cell Cycle non-Specific Drugs:
• Alkylating agents
• Antibiotics (Dactinomycin)
Effective for both
tumors) and high
Log kill hypothesis
• According to the log-kill hypothesis, chemotherapeutic
agents kill a constant fraction of cells (first order
kinetics), rather than a specific number of cells, after
1. Solid cancer tumors - generally have a low growth
fraction thus respond poorly to chemotherapy & in most
cases need to be removed by surgery
2. Disseminated cancers- generally have a high growth
fraction & generally respond well to chemotherapy
Role of Chemotherapy in Cancer
(1) Metastatic Cancer: Palliative or
(2) Adjuvant Chemotherapy:
to eradicate or control micro-metastasis
(3) Neo-adjuvant Chemotherapy:
to make Surgery of RT possible
to alleviate surgical damage
to eradicate micro-metastasis
(4) Hematological Malignancies:
1. Alkylating agents:
• Major interaction: Alkylation of DNA
• Binds to nucleophilic groups on various cell
constituents. Including DNA
• These drugs react with
carboxyl, sulfhydryl, amino, hydroxyl, and
phosphate groups of cellular constituents.
• Primary DNA alkylation site: N7 position of guanine
(other sites as well)
• Major Toxicity: bone marrow suppression
•Structurally related to normal compounds that exist
within the cell.
•Interfere with the availability of normal purine or
pyrimidine nucleotide precursors, either by inhibiting
their synthesis or by competing with them in DNA or
•Their maximal cytotoxic effects are in S-phase and
therefore are cell-cycle specific.
3. Microtubule Inhibitors:
• These are plant-derived substances .
• Cause cytotoxicity by affecting the equilibrium
between the polymerized and depolymerized
forms of the microtubules.
• Vinca alkaloids inhibit microtubule
polymerization and increase microtubule
disassembly. The mitotic spindle apparatus is
disrupted, and segregation of chromosomes in
metaphase is arrested.
4. Antineoplastic Antibiotics:
• Interacts with DNA, leading to disruption of
• Also Inhibit topoisomerases (I and II) and
produce free radicals.
• Cell-cycle nonspecific.
• Eg: Actinomycin D binds with double-stranded
DNA and blocks the action of RNA
polymerase, which prevents DNA transcription.
5. Hormonal Agents:
• Commonly involves the use of glucocorticoids.
Direct antitumor effects are related to their
• Glucocorticoids can inhibit mitosis, RNA
synthesis, and protein synthesis in sensitive
Considered cell-cycle nonspecific .
• Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
6. Monoclonal Antibodies:
• Antibodies that are made in the lab rather than by
a person's own immune system.
• Directed at specific targets and often have fewer
• Designed to recognise and find specific
abnormal proteins on cancer cells.
• Each monoclonal antibody recognizes one
• Three types of monoclonal A-bodies:
1. Trigger the immune system to attack and kill cancer
cells. E.g. Rituximab (Mabthera)
2. Stop cancer cells from taking up proteins
E.g. Trastuzumab (Herceptin).
3. Carry cancer drugs or radiation to directly to cancer
cells These are called conjugated MABs.
E.g. Ibritumomab (Zevalin)
• addition of an agent to overcome drug
resistance (eg MDR inhibitor & vinca alkaloid)
• cooperative inhibition (eg leucovorin & 5FU)
• inhibition of drug breakdown (eg DPD inhibitor
• rescue host from toxic effects of drug (eg
leucovorin following high-dose methotrexate)
Intrathecal and Intraventricular Therapy
Prolonged Intravenous Infusion Chemotherapy
Other Routes of Administration:
Body surface area
Dose to pharmacokinetic target
– Therapeutic monitoring laboratory capability
Interactions with METHOTREXATE
• Aspirin, Cotrimoxazole, Penicillin, Nsaids
Inhibition Of Tubular Secretion Of Methotrexate
Prolonged Excretion Of Methotrexate And
Interactions with 6-MERCAPTOPURINE
• 6-mercaptopurine (6-MP) or azathioprine with
• 6-MP (or azathioprine) toxicity
(thrombocytopenia, granulocytopenia) is
enhanced and may be fatal.
• The dose of 6-MP or azathioprine should be
decreased to one-third to one-fourth the
normal amount when allopurinol is used
Interactions with PHENYTOIN
• The initial decrease in phenytoin
concentration shortly after receiving various
chemotherapeutic agents and dose increase
leads to phenytoin toxicity.
• Phenytoin should have blood concentrations
measured 24-72 hours after receiving
chemotherapy and adjust the dose
ADR of Antineoplastic Drugs in Humans
Leukopenia and resulting infections
Oral or intestinal ulceration
Menstrual irregularities, including premature
menarche; impaired spermatogenesis
Teratogenesis (especially during first trimester)
Prevention or Management of Drug
• The toxicities of some anticancer drugs
can be well anticipated and hence be
prevented by giving proper medications
• mesna is given to prevent hemorrhagic
cystitis by cyclophosphamide
• Dexrazoxane, is used to reduce the risk of