Cancer chemotherapy

Question 1

Cancer

Answer 1

• 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

Question 2

Causes of cancer

Answer 2

• Environmental exposure
• Viruses
• Oncogenes
• Tumour suppressor genes

Question 3

Treatments of cancer

Answer 3

• 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.

Question 4

Number of chemo drugs

Answer 4

More than 100

-either alone or in combination with other drugs or treatments

Question 5

Chemo drugs vary widely based on

Answer 5

• chemical composition
• route of administration
• type of cancer targeted
• side effects

Question 6

Primary induction chemo

Answer 6

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).

Question 7

Neoadjuvant chemo

Answer 7

in patients with localised cancer
for which alternative local therapies, e.g. surgery, exist but which are
less than completely effective.

Question 8

Adjuvant chemo

Answer 8

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)

Question 9

Main goal of antineoplastic agents is

Answer 9

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

Question 10

Therapeutic index

Answer 10

LD50 / ED50

-lethal dose of a drug for 50% of pop (LD50) divided by min effective dose for 50% of pop (ED50)

Question 11

Chemotherapy: to acheive a cure

Answer 11

TOTAL CELL KILL must be tried
• Early diagnosis and early institution of treatment
• Combination chemotherapy
• Intermittent regimens
• Adjuvant and neoadjuvant chemotherapy occasionally

Question 12

Log-kill hypothesis

Answer 12

• 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

Question 13

Cell cycle

Answer 13

• 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

Question 14

Cell cycle drugs

Answer 14

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

Question 15

Alkylating agents

Answer 15

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

Question 16

Examples of alkylating agents

Answer 16

Busulfan
Lomustine
Decarbazine

Question 17

Resistance to alkylating agents

Answer 17

• Increased activity of DNA repair enzyme
• Increase metabolic inactivation of the drug
• Decrease influx of the drug

Question 18

Platinum analogues

Answer 18

• 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

Question 19

Platinum analogues examples

Answer 19

Cisplatic (non cell cycle specific)

Question 20

Antimetabolites

Answer 20

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

Question 21

Antimetabolites examples

Answer 21

• Folates antagonist (i.e. Methotrexate)
• Purine antagonists (i.e. 6 Mercaptopurine)
• Pyrimidine antagonist (i.e. 5 Fluorouracile)

Question 22

Methotrexate (folic acid analogue)

Answer 22

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

Question 23

Vinca alkaloids

Answer 23

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

Question 24

Vinca alkaloids examples

Answer 24

Vincristine

Vinblastine

Question 25

Taxanes

Answer 25

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

Question 26

Taxanes examples

Answer 26

Paclitaxel

Question 27

Antitumour antibiotics

Answer 27

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

Question 28

Antitumour antibiotics examples

Answer 28

Doxorubicin (Anthracycline) Mitomuycin C (CCNS) Bleomycin (CCS)

Question 29

Hormones and antagonists

Answer 29

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

Question 30

Bisphosphonates

Answer 30

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)

Question 31

Bisphosphonate mechanism

Answer 31

• 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

Question 32

Drug combination

Answer 32

• 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

Question 33

Drug combination efficacy

Answer 33

only drugs known to be somewhat effective when used alone

Question 34

Drug combination toxicity

Answer 34

can’t overlap between drugs. The selection may add up the | adverse effect but minimize the risk of lethal effect

Question 35

Drug combination optimum scheduling

Answer 35

Optimal dose and schedule of each drug should | be used and drug combination should be given at consistent intervals

Question 36

Drug combination mechanisms of interaction

Answer 36

Maximal effect is achieved with a clear understanding of biochemical, molecular and pharmacokinetics mechanisms and interaction between the individual drugs

Question 37

Drug combination avoidance of arbitrary dose changes

Answer 37

risk to go below the threshold of effectiveness and risk to destroy the ability of the combination to cure disease in a given patient

Question 38

Drug resistance

Answer 38

• 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