Cancer Part 2 Flashcards
State the limit to the usefulness of cytotoxic chemotherapy
Access
Side effects
Resistance
End-point
Cytotoxic agents are alkylating agents. True/false?
True
state the physical barrier to the use of cytotoxic chemotherapy
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
IV cytotoxic agents can stimulate the vomiting reflex via systemic circulation. True/False
True
State how cytotoxic drugs can cause damage to the GIT
Mucositis/mouth ulcers:- painful inflammation of oral mucosa - leads to ulcers, fungal infection, speech/eating/swallowing difficulties.
Cytotoxic agents can damage the haemopoietic system. True/False
True
Describe how Cytoxic agents can lead to myelosuppression
Effects of tumour itself/RT
Difficult to recognise in neutropaenic patient - fever only
Opportunistic infections - fungal and viral
Treatment of Myleosupreesion(bone marrow damage)
Timing of doses/haemopoietic monitoring
Transfusions - blood granulocytes, platelets, autologous blood/marrow
CSF’s - accelerate bone marrow recovery
State how to prevent myelosuppression
Avoid exposure to infection
Patients do better at home
Avoid infected people/crowds
Watch kitchen hygiene
Facts about hair loss in cytotoxic chemotherapy
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
CT agents can sterilize patients during cancer therapy. True/false?
True
Renal toxicity with cis platin can be treated with ?
Mannitol diuresis
Haemorrhagic cystitis with ifosfamide and cyclophosphamide can be treated with?
Diuresis
State how to manage carCardiotoxicity with doxorubicin
careful ECG monitoring
many cytotoxic agents are mutagenic eg alkylating agents. True or false?
True
cytotoxic agents can lead to what disease?
treatment-induced neoplasia, often leukaemias
Treatment-induced neoplasia develops after how many years?
10-15years later
list the possible mechanisms of anti-cancer drug resistance
see slide 14
facts about drug resistance
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
Facts about cancer treatment end point
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?
List the two groups of the cytotoxic agent
Cell cycle-specific
cell cycle non specific
Describe cell cycle-specific drugs
Schedule dependent - can be given as infusion and allow cells to progress into drug sensitive phase
Describe Cell cycle (phase) non-specific
Can give drugs at any phase of the cell cycle
Dose-dependent - Activity dependent on dose
Facts about the administration of anti cancer agents
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
What are alkylating agents?
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)
What makes alkylating agents effective?
Effective by binding covalently to nucleophilic groups
N7 and O6 of guanine
N1 and N3 of adenine
N3 of cytosine
What position is probably the most critical for cytotoxic action in alkylating agent
Guanine N7 position
what is the mechanism of action of alkylating agent
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
facts about Nitrogen Mustard
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.
Describe how alkylating agents work
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
Most alkylating agents are bifunctional. True/false?
True
List the side effects of Alkylating agents
Extravasation damage
N & V
Mucositis
Myelosuppression
Alopecia
Depressed gametogenesis
Increased risk of non-lymphocytic leukaemia
Drug handling/waste handling
Facts about Nitrogen Mustard
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
List the side effect of Mechlorethamine
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
The most generally useful alkylating agent is called?
Cyclophosphamide & ifosfamide
Cyclophosphamide is administered via what route?
Oral
What is the route of administration of Ifosfamide?
IV
both Cyclophosphamide and Ifosfamide are prodrugs activated by?
hepatic P450 - liver unharmed
Resistance to alkylating drugs occurs from?
Increased DNA repair
Increased production of thiols (glutathione)
state how alkylating drugs are used
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
List toxicity associated with Alylating drugs
N/V/D
Alopecia
Myelosuppression
Haemorrhagic cystitis - fibrosis of bladder - due to acrolein
Amenoohoea/sterility
Secondary malignancies
List the side effects that are less significant in Cyclophoshamide
N and V
Alopecia
Chlorambucil is an alkylating agent indicated for ?
Oral admin for lymphocytic leukaemias – esp CLL
State the role of a carrier in Chlorambucil
Carrier molecule delays activation of drug - better distribution
State the name of an alkylating agent indicated for Myeloma and Ovarian?
Melphalan
A carrier target for melanoma seen in Mephalan is known as
Phenylalanine
List examples of other mustards?
Uramustine, oestramustine
Are Nitrogen mustards able to cross the blood brain barrier?
No because they are too polar but Nitosoureas have been developed to address this
an example of a Nitrourea is ?
Carmustine
