Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

CHEMOTHERAPY > Alkylating Agents > Flashcards

Alkylating Agents Flashcards

1
Q

Name the alkylators

  1. Classical (nitrogen mustards/nitrosoureas)
  2. Non-classical/other
A

Nitrogen mustards: chlorambucil, cyclophosphamide, mechlorthamine, melphalan, ifosfamide

Nitrosoureas: CCNU, BCNU, streptozotocin

Other: Procarbazine, dacarbazine (DTIC), temozolomide, busulfan, Aziridines (thio-TEPA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

MOA:

A

MOA:
1. Act through covalent binding of ALKYL groups (-CH2Cl) to intracellular molecules

  1. Generate highly reactive positively charged intermediates – > these combine with ELECTRON RICH NUCLEOPHILIC GROUPS (ie amino, phosphate, sulfhydryl, hydroxyl moieties)

**Nucleophilic groups are potential sites of alkylation on almost all biologic molecules

**Alkylation of BASES in DNA is major cause of toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Activity of most alkylators enhanced by these 5 things:

A

Enhance alkylator activity:

  1. Radiation
  2. Hyperthermia
  3. Nitroimidazoles
  4. Glutathione depletion
  5. DNA repair inhibition
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Alkylating reactions can occur by 2 mechanisms SN1 and SN2. Describe each.

A

SN1 (1) rate limiting step = formation of carbonium ion that can rapidly react with a nucleophile (2) follows 1st order kinetics t/f rate depends solely on CONCENTRATION of alkylating agent

SN2 - follow second order kinetics, t/f rate depends on concentration of both alkylating agent AND nucleophile

NOTE: nucleophiles donate electrons to form chemical bonds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the main differences between monofunctional and difunctional alkylators?

A
  1. Alkylators are mono- or bifunctional (ie contain 1 or 2 reactive groups)
  2. Only bifunctional agents can form crosslinks between biological molecules (t/f most useful)
  3. Bifunctional agents – > DNA interstrand crosslinks that prevent cell replication unless repaired
  4. Monofunctional agents – > cytotoxic via mismatch-repair mediated processes (cells lacking MMR are methylating tolerant)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Why do cells with mutated p53 have greater resistance to alkylating agents?

A

DNA checkpoint proteins (p53) are responsible for recognition of DNA alkylation and strand breaks.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Most alkylators enter cells by X; exceptions include X and X

A

Many alkylators are LIPID soluble and enter cells by PASSIVE DIFFUSION.

Exceptions include:
1. Mechlorethamine - uptake depends on CHOLINE TRANSFER SYSTEM

  1. Melphalan - transported by at least two transport systems that carry LEUCINE and other AAs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Are alkylators cell cycle specific or non-specific?

A

Alkylators are cell-cycle NON-SPECIFIC since they bind directly to DNA.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Sensitivity to alkylators depends on X (pharmacokinetics)

A

Dependent on AUC (is relatively independent of schedule of administration)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What does monofunctional mean?

A

one reactive group

  • -causes single strand breaks in DNA
  • -damages bases by inducing abnormal base pairing
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

alkylation at N7 results in what?

A

alkylation at N7 results in conformation changes (base pairing G-T; gene miscoding) - mispairing!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Resistance to alkylators (general, from T&H)

6

A
  1. Decreased transport across membrane
  2. Increased intracellular thiol concentrations (ie glutathione) – > work by reacting w alkylating agents and reduce likelihood of interacting w DNA
  3. Increased detoxification of reactive intermediates
  4. Alterations in DNA repair enzymes (ie guanine-06-alkyltransferase)
  5. defects in cell cycle arrest/apoptosis
  6. increased AKT expression – > leads to inhibition of apoptosis and p53
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Name the bifunctional alkylators (2 chloroethyl groups, able to crosslink):

A

The nitrogen mustards (mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide)
BCNU (a nitrosourea)
Busulfan?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Name the monofunctional alkylators (1 chloroethyl group)

A

CCNU

Procarbazine, dacarbazine, temozolamide, aziridines (thio-TEPA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Nitrogen mustard MOA (with regard to bifunctionality)

A
  1. Nitrogen mustards are bifunctional with TWO CHLOROETHYL GROUPS – > 1 group undergoes first order reaction and loses a Cl – > becomes a highly reactive positive intermediate
  2. The intermediate can bind covalently to electronegative group on DNA base = ALKYLATION
  3. The other group can become reactive intermediate and bind another base = INTERSTRAND CROSSLINKING
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the site of alkylation for nitrogen mustards?

A

N7 position of guanine – > can lead to mispairing with thymine or to strand breakage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Is chlorambucil more toxic to cycling or non-cycling cells?

A

Equally toxic to cycling and non-cycling cells – > may lead to delayed or cumulative effect on bone marrow dt toxicity of hematopoietic cells.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Is melphalan absorption predictable or unpredicatable?

A

Melphalan absorption is unpredictable - some respond IV when don’t PO

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

How is melphalan detoxified?

Any concerns for organ dysfunction?

A

Melphalan detoxified via SPONTANEOUS HYDROLYSIS but increased toxicity seen with RENAL dysfunction

20
Q

How is melphalan uptake into cells mediated?

A

AA active transport system - resistance to melphalan may develop dt changes w this system

21
Q

Is melphalan more toxic to cycling or non-cycling cells?

A

Melphalan is equally toxic to cycling and non-cycling cells – > may lead to delayed or cumulative effect on bm dt toxicity to hematopoietic cells

22
Q

Do cells with mutated p53 have greater or less resistance to alkylating agents?

A

Cells with mutated p53 have GREATER resistance to alkylators.

23
Q

Name 4 mechanisms of resistance to nitrogen mustards (chabner)

A
  1. increased capacity to repair alkylated lesions (ex: O6-alkyl transferase - nitrosoureas, busulfan)
  2. increased expression of glutathione-associated enzymes
  3. increased ALDH (cyclophosphamide)
  4. Decreased expression or mutation of p53
24
Q

What is the oral bioavailability of cyclophosphamide, ifosfamide, melphalan, busulfan?

A

cyclophosphamide 100%, ifosfamide none, melphalan 30% variable, busulfan 50% +

25
Q

Which nitrogen mustards require activation (and how)?

A

Cyclophosphamide and ifosfamide require activation by microsomal hydroxylation

  1. cyclophosphamide - (hep micros oxidation) - > 4-hydroxycyclophosphamide –> aldophosphamide -(spont)- > phosphoramide mustard + acrolein
  2. Ifosfamide…..ifosphoramide mustard + acrolein
26
Q

What is cyclophosphamide’s DNA crosslinker (metabolite) of clinical significance?

A

phosphoramide mustard

27
Q

What does inactive cyclophosphamide become oxidized to?

A

4-hydroxycyclophosphamide (via hepatic microsomal oxidation)

28
Q

What is a mechanism of resistance that is significant for the nitrosoureas but not the nitrogen mustards?

A

mismatch repair deficiency

29
Q

MOA streptozotocin

A

unique methylnitrosourea with methylating activity that lacks carbamoylating activity

30
Q

DLT in humans for streptozotocin

A

GI and renal - NOT hematopoietic

31
Q

Are the nitrosoureas mono or bifunctional alkylators?

A

BCNU - bifunctional (must give IV)
CCNU - monofunctional (can give PO)
Streptozotocin - neither? its a methylnitrosourea

32
Q

The “other” alkylators - procarbazine, dacarbazine, temozolomide, aziridines (thio-TEPA) - what is the key site of DNA attack?

A

O6 methyl group of guanine

33
Q

What is the key site of DNA attack for busulfan?

A

N7 methyl group of guanine

34
Q

What is the key site of DNA attack for the nitrosoureas?

A

In general O6 methyl group of guanine for CCNU, BCNU (streptozotocin).

35
Q

name the chloronitrosourea(s)

name the methylnitrosourea(s)

A

chloro - CCNU, BCNU

methyl - streptozotocin

36
Q

What is a side effect that may be seen with ifosfamide but not with cyclophosphamide?

A

neurotoxicity

37
Q

What metabolite of cyclophosphamide enters cells?

A

4-hydroxycyclophosphamide enters cells then spontaneously decomposes to phosphoramide mustard and acrolein

38
Q

What enzyme can detoxify 4-hydroxycyclophosphamide?

A

4-hydroxycyclophosphamide can
1 - spontaneously decompose to phosphoramide mustard and acrolein

OR

2 - be detoxified to ALDEHYDE DEHYDROGENASE to form inactive metabolites

39
Q

How is most of cyclophosphamide eliminated?

A

RENAL EXCRETION of INACTIVE metabolites

renal clearance of active metabolites is very low - don’t need dose reduction w renal disease

40
Q

Does cyclophosphamide induce cytochrome P450?

A

Yes. It will induce its own metabolism w repeat administration, which ALTERS the RATE but NOT the absolute amount of phosphoramide mustard formation

41
Q

DLT of cyclophosphamide?

A

BM suppression - BUT is STEM CELL and PLATELET SPARING

note: cardiotoxicity is dlt in high doses needed for bmt

42
Q

Nitrosoureas are ____ _____, so they penetrate the CNS

A

lipid soluble

43
Q

Which of the following are prodrugs?

Ifosfamide
Cyclophosphamide
Procarbazine
Dacarbazine
Temozolomide
Melphalan
Chlorambucil
A

All EXCEPT

Melphalan
Chlorambucil

44
Q

An increased amount of which enzyme will confer resistance to procarbazine?

A

MGMT (O6 methylguanine methyl transferase)

45
Q

Is dacarbazine a purine antimetabolite?

A

NO, eventho this is what it was developed for

CHEMOTHERAPY (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions