Cancer Part 2

Question 1

State the limit to the usefulness of cytotoxic chemotherapy

Answer 1

Access
Side effects
Resistance
End-point

Question 2

Cytotoxic agents are alkylating agents. True/false?

Answer 2

True

Question 3

state the physical barrier to the use of cytotoxic chemotherapy

Answer 3

Chaotic nature of tumour blood vessels and blood flow
Composition of tumour interstitium
Disturbed convection/diffusion into interstitial space of tumours:-
High tumour interstitial pressure (IP)
Tumour hyperthermia
Necrotic interstitium

Question 4

IV cytotoxic agents can stimulate the vomiting reflex via systemic circulation. True/False

Answer 4

True

Question 5

State how cytotoxic drugs can cause damage to the GIT

Answer 5

Mucositis/mouth ulcers:- painful inflammation of oral mucosa - leads to ulcers, fungal infection, speech/eating/swallowing difficulties.

Question 6

Cytotoxic agents can damage the haemopoietic system. True/False

Answer 6

True

Question 7

Describe how Cytoxic agents can lead to myelosuppression

Answer 7

Effects of tumour itself/RT
Difficult to recognise in neutropaenic patient - fever only
Opportunistic infections - fungal and viral

Question 8

Treatment of Myleosupreesion(bone marrow damage)

Answer 8

Timing of doses/haemopoietic monitoring
Transfusions - blood granulocytes, platelets, autologous blood/marrow
CSF’s - accelerate bone marrow recovery

Question 9

State how to prevent myelosuppression

Answer 9

Avoid exposure to infection
Patients do better at home
Avoid infected people/crowds
Watch kitchen hygiene

Question 10

Facts about hair loss in cytotoxic chemotherapy

Answer 10

Loss of hair - often seen after 1-2 weeks, reversible
Scalp tourniquets or chilling of the scalp can be used
Patients can:-
Cut hair short
No strong chemicals
No aggressive brushing/towelling/hair drying
Wigs available but expensive for good ones

Question 11

CT agents can sterilize patients during cancer therapy. True/false?

Answer 11

True

Question 12

Renal toxicity with cis platin can be treated with ?

Answer 12

Mannitol diuresis

Question 13

Haemorrhagic cystitis with ifosfamide and cyclophosphamide can be treated with?

Answer 13

Diuresis

Question 14

State how to manage carCardiotoxicity with doxorubicin

Answer 14

careful ECG monitoring

Question 15

many cytotoxic agents are mutagenic eg alkylating agents. True or false?

Answer 15

True

Question 16

cytotoxic agents can lead to what disease?

Answer 16

treatment-induced neoplasia, often leukaemias

Question 17

Treatment-induced neoplasia develops after how many years?

Answer 17

10-15years later

Question 18

list the possible mechanisms of anti-cancer drug resistance

Answer 18

see slide 14

Question 19

facts about drug resistance

Answer 19

Multidrug resistance (MDR)
Amplified gene product (MDR-1 gene)
Codes for transmembrane P-glycoprotein (P170)
ATP-dependent efflux pump, high levels in liver, pancreas, colon, lung, renal
Imparts intrinsic resistance to many chemotherapeutic agents
Inert pump blockers being sought

Question 20

Facts about cancer treatment end point

Answer 20

Once at <10^9 cells tumour no longer palpable
Below <10^7 cells, no longer visible by x-ray

Patient might think that he/she is cured, bulk of tumour still present
Pretreatment with surgery/RT decreases tumour mass, fewer ‘rounds’ of CT, before resistance/toxicity forces therapy to stop

When do you stop treatment and leave the body to eliminate the residual cells?

Question 21

List the two groups of the cytotoxic agent

Answer 21

Cell cycle-specific
cell cycle non specific

Question 22

Describe cell cycle-specific drugs

Answer 22

Schedule dependent - can be given as infusion and allow cells to progress into drug sensitive phase

Question 23

Describe Cell cycle (phase) non-specific

Answer 23

Can give drugs at any phase of the cell cycle
Dose-dependent - Activity dependent on dose

Question 24

Facts about the administration of anti cancer agents

Answer 24

Combination chemotherapy
Co-therapy using drugs with minimal overlapping mechanisms of action and toxicities
Alternate myelosuppresive and non- myelosuppresive drugs
Continuous antineoplastic effect
Allows bone marrow recovery

Question 25

What are alkylating agents?

Answer 25

Cell cycle non-specific agents - but proliferating cells most sensitive (G1 and S) Toxic to any rapidly dividing cells Transcription affected and protein synthesis suppressed Alkylating agents used in combination - solid and lymphatic tumours Mutagenic and carcinogenic - secondary malignancy (acute leukaemia)

Question 26

What makes alkylating agents effective?

Answer 26

Effective by binding covalently to nucleophilic groups N7 and O6 of guanine N1 and N3 of adenine N3 of cytosine

Question 27

What position is probably the most critical for cytotoxic action in alkylating agent

Answer 27

Guanine N7 position

Question 28

what is the mechanism of action of alkylating agent

Answer 28

Inter-strand cross-linking of DNA strands - stops strand separation Intra-strand cross-linking Base ring cleavage - strand cleavage De-purination - strand cleavage Tautomeric mutation - G pairs with T, GC to AT in daughter cells Ineffective repair - frameshift mutation

Question 29

facts about Nitrogen Mustard

Answer 29

Bischloroethylamines - developed from sulphur/nitrogen cmpds used for chemical warfare during WWI (HCl is released into lungs of the victim) Survivors developed lymphocytopaenia Drug developed in the 1940s for Hodgkins leukaemia.

Question 30

Describe how alkylating agents work

Answer 30

Undergo intramolecular cyclisation forming an unstable ethylene immonium cation Tertiary amine is transformed into quaternary ammonium cmpd Ring opens out to form reactive carbonium ion which performs the alkylation Carbonium ion is unstable reacts with an electron donor

Question 31

Most alkylating agents are bifunctional. True/false?

Answer 31

True

Question 32

List the side effects of Alkylating agents

Answer 32

Extravasation damage N & V Mucositis Myelosuppression Alopecia Depressed gametogenesis Increased risk of non-lymphocytic leukaemia Drug handling/waste handling

Question 33

Facts about Nitrogen Mustard

Answer 33

Mechlorethamine - one of the most potent antineoplastic agents Very unstable (T1/2 < 10 mins via iv) Given as part of MOPP regime Mechlorethamine Oncovin Prednisone Procarbazine Little drug excreted Effective vs Hodgkins Palliative use for bronchus, ovary, breast, and other solid tumours

Question 34

List the side effect of Mechlorethamine

Answer 34

All those already mentioned Centrally mediated N & V and bone marrow effects can be severe and dose limiting Extravasation is a problem – reactivity at injection site

Question 35

The most generally useful alkylating agent is called?

Answer 35

Cyclophosphamide & ifosfamide

Question 36

Cyclophosphamide is administered via what route?

Answer 36

Oral

Question 37

What is the route of administration of Ifosfamide?

Answer 37

IV

Question 38

both Cyclophosphamide and Ifosfamide are prodrugs activated by?

Answer 38

hepatic P450 - liver unharmed

Question 39

Resistance to alkylating drugs occurs from?

Answer 39

Increased DNA repair Increased production of thiols (glutathione)

Question 40

state how alkylating drugs are used

Answer 40

oral admin, singly or in combo for a variety of neoplastic disease Burkitt’s lymphoma and other lymphomas ALL (acute lymphoblastic leukaemia) Breast cancer Several others Can be given i.v., i.m. and by regional perfusion

Question 41

List toxicity associated with Alylating drugs

Answer 41

N/V/D Alopecia Myelosuppression Haemorrhagic cystitis - fibrosis of bladder - due to acrolein Amenoohoea/sterility Secondary malignancies

Question 42

List the side effects that are less significant in Cyclophoshamide

Answer 42

N and V Alopecia

Question 43

Chlorambucil is an alkylating agent indicated for ?

Answer 43

Oral admin for lymphocytic leukaemias – esp CLL

Question 44

State the role of a carrier in Chlorambucil

Answer 44

Carrier molecule delays activation of drug - better distribution

Question 45

State the name of an alkylating agent indicated for Myeloma and Ovarian?

Answer 45

Melphalan

Question 46

A carrier target for melanoma seen in Mephalan is known as

Answer 46

Phenylalanine

Question 47

List examples of other mustards?

Answer 47

Uramustine, oestramustine

Question 48

Are Nitrogen mustards able to cross the blood brain barrier?

Answer 48

No because they are too polar but Nitosoureas have been developed to address this

Question 49

an example of a Nitrourea is ?

Answer 49

Carmustine