Cancer chemotherapy Flashcards
Cancer
• Cancer is the second leading cause of mortality
• Continuous uncontrolled growth of cells
• A tumour is any abnormal proliferation of cells
• Benign tumours stays confined to its original location
• Malignant tumours are capable of invading surrounding tissue or
invading the entire body
• Tumours can arise from any cell type in the body and are classified
as to their cell type
Causes of cancer
- Environmental exposure
- Viruses
- Oncogenes
- Tumour suppressor genes
Treatments of cancer
• Surgery or
• Radiotherapy
-mainly possible when tumour remains localised at diagnosis
• Chemotherapy - once cancer metastasizes chemotherapy is
required for effective cancer management.
• Chemotherapy is often combined with radiotherapy to allow
surgical resection to take place.
Number of chemo drugs
More than 100
-either alone or in combination with other drugs or treatments
Chemo drugs vary widely based on
- chemical composition
- route of administration
- type of cancer targeted
- side effects
Primary induction chemo
when it is administered in
patients with advance cancer for which no alternative treatment
exists. Can be curative in only a small subset of patients who present
with advance disease. (i.e. Hodgkin’s and non-Hodgkin’s lymphoma
in adults or lymphoblastic leukemia in children).
Neoadjuvant chemo
in patients with localised cancer
for which alternative local therapies, e.g. surgery, exist but which are
less than completely effective.
Adjuvant chemo
as an adjuvant to local therapy such as
surgery or radiation. Is effective in prolonging both disease-free and
overall survival in patients with different type of cancer (i.e. patients
with breast, colon gastric or non-small lung cancer)
Main goal of antineoplastic agents is
to eliminate the cancer
cells without affecting normal tissues
-in reality, all cytotoxic drugs affect normal tissues as well as
malignancies - aim for a favorable therapeutic index
Therapeutic index
LD50 / ED50
-lethal dose of a drug for 50% of pop (LD50) divided by min effective dose for 50% of pop (ED50)
Chemotherapy: to acheive a cure
TOTAL CELL KILL must be tried
• Early diagnosis and early institution of treatment
• Combination chemotherapy
• Intermittent regimens
• Adjuvant and neoadjuvant chemotherapy occasionally
Log-kill hypothesis
• Chemotherapeutic agents kill a constant
PROPORTION of tumour cell population
(first order kinetics), rather than a constant
NUMBER of cells, after each dose
• Solid cancer tumours – generally have a low
growth fractions thus respond poorly to
chemotherapy and in most cases need to be removed by surgery
• Disseminated cancers- generally have a high
growth fraction and generally respond well
to chemotherapy
Cell cycle
• Several anticancer effective drugs exert their action on cells
traversing the cell cycle and are called Cell Cycle- Specific (CCS)
• Cell-Cycle-Non Specific (CCNS) drugs that can sterilize tumour cells
whether they are cycling or resting in the G0 compartments
Cell cycle drugs
Cell cycle specific (CCS) -antimetabolites (S phase) -taxanes (M phase) -vinca alkaloids (M phase) -antimicrotubule inhibitor (M phase) -antitumous antibiotics (G2-M phase) Cell cycle non specific (CCNS) -alkylating agents -antitumour antibiotics -campothecins -platinum analogs -anthracyclins
Alkylating agents
Carcinogenic in nature and can
increase the risk of secondary
malignancies
Form reactive carbonium ion –> transfer alkyl gps to nucleophilic sites on DNA bases
-cross linkage
-abnormal base pairing
-DNA strand breakage –> reduces cell proliferation
• Used to treat a wide variety of hematologic and solid tumour
(i.e. ovarian cancer, brain tumours)
• Immunosuppressant action
• Most of the adverse effects are generally dose-related and occur
primarily in rapidly growing tissues
• Bone marrow depression
• Nausea and Vomiting. Antiemetics are often given prior and after
alkylating agents dosing
Examples of alkylating agents
Busulfan
Lomustine
Decarbazine
Resistance to alkylating agents
- Increased activity of DNA repair enzyme
- Increase metabolic inactivation of the drug
- Decrease influx of the drug
Platinum analogues
• Mechanisms of action not completely clear
• Thought to exerts their cytotoxic effect similarly to alkylating
agents
Form highly reactive platinum complexes –> intra strand and interstrand cross-link –> DNA damage –> inhibits cell proliferation
Platinum analogues examples
Cisplatic (non cell cycle specific)
Antimetabolites
Act on intermediary metabolism of proliferating cells.
Interfere with DNA and RNA growth by substituting for the
normal building blocks of RNA and DNA (S phase).
Specifically designed and synthesized based on the
knowledge of critical cellular processes involved in DNA
biosynthesis
Antimetabolites examples
- Folates antagonist (i.e. Methotrexate)
- Purine antagonists (i.e. 6 Mercaptopurine)
- Pyrimidine antagonist (i.e. 5 Fluorouracile)
Methotrexate (folic acid analogue)
Binds to the active catalytic site of dihydrofolate reductase (DHFR)
Inhibiting the synthesis of tetrahydrofolate (THF)
Interfering with formation of DNA, RNA and key cellular proteins
Poor brain penetration, remains in tissue longer than folate prolonging
the inhibitor effect. Remains unchanged in urine
Actions- Cytotoxic, mainly on bone marrow
Immunosuppressive, preventing clonal expansion of B and T
lymphocytes
Anti-Inflammatory
Adverse effect- Megaloblastic anemia, leuokopenia, alopecia,
nephropathy
Vinca alkaloids
Natural products, are alkaloid that derive from the
periwinkle plant Vinca Rosea.
Act by inhibiting tubulin proliferation, which disrupt assembly of
microtubules. This results in mitotic arrest in metaphase, bringing cell
division to a halt and ultimately leading to CELL DEATH
Vinca alkaloids examples
Vincristine
Vinblastine
Taxanes
Alkaloid ester derived from the Pacific yew
(Taxus brevifolia) and the European yew (Taxus
baccata)
Act by enhancing tubulin polymerization. This promotion of
microtubules assembly occurs in absence of microtubules-associated
proteins and guanosine triphosphate, resulting in inhibition of mitosis
and cell division
Taxanes examples
Paclitaxel
Antitumour antibiotics
Bind to DNA through intercalation between specific bases
-block synthesis of RNA, DNA or both
-DNA strand scission
-interfere with cells replication
All cancer antibiotics now used in clinical practice from soil microbe Streptomyces
Antitumour antibiotics examples
Doxorubicin (Anthracycline)
Mitomuycin C (CCNS)
Bleomycin (CCS)
Hormones and antagonists
Glucocorticoids: used in acute leukemia and lymphomas due to their marked
lympholytic effect
Estrogens: physiological antagonists of androgens, so used to antagonize the effect
of androgens in androgen dependent prostate cancer
Estrogens antagonists: used in breast cancer. Selective Estrogen Receptor (ER) Modulators, or
ER down regulator. Adverse effect, hot flushes, vomiting, menstrual
irregularities
Bisphosphonates
Bone metastases are a common occurrence in patients with advanced
solid tumours.
Metastasis to the skeleton occurs in the majority of
patients with multiple myeloma and metastatic breast,
prostate, and thyroid cancers
Spread of cancer to bone is associated with:
• pain, hypercalcemia, anemia,
• increased risk of infection,
• compression of the spinal cord and/or nerve
roots,
• decreased mobility and skeletal fracture
(catastrophic)
Bisphosphonate mechanism
• Slow down the rate of growth of bone crystal and their resolution
• Reduce morbidity from bone metastasis by reducing skeletal events.
• Lower calcium levels.
• After IV administration approximately 25–40% is excreted by the kidney, and the
remainder is taken up by bone.
• Poor oral bioavailability
• As they bind to calcium in the diet can cause gastrointestinal toxicities such as
nausea, vomiting, indigestion, oesophagitis, and diarrhea
Drug combination
• Developed in the 1960s-1970s based on the knowledge of the
biochemical actions of anticancer drugs rather than on their clinical
effects.
• Provides maximal cell kill within a range of toxicity tolerated by the
host for each drug without compromising the dosing.
• Provides broader range of interactions between drugs and tumour
cells with different genetic abnormalities in a heterogeneous
tumour population
• Has the potential to prevent or slow the subsequent development
of cellular drug resistance
Drug combination efficacy
only drugs known to be somewhat effective when used alone
Drug combination toxicity
can’t overlap between drugs. The selection may add up the
adverse effect but minimize the risk of lethal effect
Drug combination optimum scheduling
Optimal dose and schedule of each drug should
be used and drug combination should be given at consistent intervals
Drug combination mechanisms of interaction
Maximal effect is achieved with a clear
understanding of biochemical, molecular and pharmacokinetics
mechanisms and interaction between the individual drugs
Drug combination avoidance of arbitrary dose changes
risk to go below the threshold
of effectiveness and risk to destroy the ability of the combination to
cure disease in a given patient
Drug resistance
• Critical in chemotherapy
• Some tumour (i.e. malignant melanoma and brain tumour) exhibit primary
resistance.
• In contrast acquired resistance develops in response to exposure to a given
anticancer agent.
Can be highly specific to a single drug, mainly based on a specific change in the genetic
machinery of a given tumour cell with amplification or increased expression of one or
more gene.
Multidrug-resistant phenotype can occur, resulting in enhanced drug efflux and
reduced intracellular accumulation of a broad range of structurally unrelated
anticancer agents (i.e. taxanes, vinca alkaloid, anthracycline).
Several other mechanism i.e. drug is not metabolized to an active form; drug is
inactivated; drug target is increased (increased level of enzyme or gene amplification);
alternative biochemical pathways are increased
