Cytotoxic Chemotherapy

Question 1

in which phases of the cell cycle do cells proliferate?

Answer 1

S, G2 and M

Question 2

in what phases of the cell cycle do cells differentiate or remain quiescent?

Answer 2

G0

G1

Question 3

when does DNA synthesis occur?

Answer 3

S phase

Question 4

classification of cytotoxic drugs?

Answer 4

cell cycle specific

non-cell cycle specific

Question 5

general characteristics of cell cycle specific agents?

Answer 5

tumour specific (relatively)
duration of exposure more important than dose

Question 6

types of cell cycle specific agents?

Answer 6

antimetabolites (impair nucleotide synthesis/incorporation)

mitotic spindle inhibitors

Question 7

examples of antimetabolites?

Answer 7

methotrexate (inhibits dihydrofolate reductase)
6-mercaptopurine/cytosine arabinoside/fludarabine (incorporated into DNA)
hydroxyurea (impaired deoxynucleotide synthesis - ribonucleotide reductase)

Question 8

why are dihydrofolate reductase and ribonucleotide reductase targeted?

Answer 8

dihydrofolate reductase = folate metabolism
ribonucleotide reductase = nucleotide synthesis
both involved in formation of nucleotide pool leading to new DNA strand synthesis

Question 9

what enzyme unwinds DNA?

Answer 9

topisomerase II

Question 10

examples of mitotic spindle inhibitors?

Answer 10

vinca alkaloids (vincristine/vinblastine)
taxotere (taxol)
both are plant derivatives

Question 11

general characteristics of non-cell cycle specific agents?

Answer 11

non-tumour specific so damage normal stem cells

cumulative dose more important than duration

Question 12

examples of non-cell cycle specific agents?

Answer 12

alkylating agents (e.g chlorambucil/melphalan)
platinum derivatives (cis-platinum/carboplatin)
cytotoxic antibiotics (anthracyclines)

Question 13

how do alkylating agents work?

Answer 13

• bind covalently to bases of DNA (adducts)

- produce DNA strand breaks (Mutation) by free radical production

Question 14

how do cytotoxic antibiotics work?

Answer 14

DNA intercalation (reversible)
impairs RNA transcription
strand breaks in DNA (free radicals)

Question 15

general imediate side effects of cytotoxic drugs?

Answer 15

(affects rapidly dividing organs)
bone marrow suppression
gut mucosal damage
hair loss

Question 16

drug specific side effects?

Answer 16

vinca alkaloids = neuropathy
anthracyclines = cardiotoxic
cis-platinum = nephrotoxic

Question 17

long term side effects of alkylating agents?

Answer 17

infertility

secondary malignancy

Question 18

long term side effects of anthracyclines?

Answer 18

cardiomyopathy

Question 19

what is combination chemotherapy?

Answer 19

combination of non-cross resistant drugs with non-overlapping toxicity spectra
results in additive/synergistic mechanisms of action

Question 20

why can chemo fail?

Answer 20

slow tumour doubling time
tumour sanctuaries
can have drug resistant mechanisms (decreased drug accumulation, altered drug metabolism, increased DNA repair, altered gene expression)

Question 21

intensifying chemo is limited by what?

Answer 21

the myelosuppression caused

Question 22

how is myelosuppression due to chemo overcome?

Answer 22

use of haematopoietic growth factors
combine myelosuppressive and non-myelosuppressive agents
intensify doses of active drugs + stem cell rescue

Question 23

sources of stem cells for transplantation?

Answer 23

tissue source (blood vs bone marrow)
patient source (autologous or allogenic - sibling or unrelated match)

Question 24

steps in progenitor/stem cell transplant?

Answer 24

blood/bone marrow cell collection > myeloablative therapy (destroy immune system) > reinfusion of progenitor/stem cells > bone marrow regenerates

Question 25

what is the philedelphia chromosome?

Answer 25

balanced translocation in chromosome 22

22Q11

Question 26

treatment of chronic myeloid leukaemia (CML)?

Answer 26

targeted therapy with tyrosine kinase
very successful with few needing stem cell transplant
patients can achieve complete molecular responses and have prospect of stopping treatment