Antineoplastics 2

Question 1

What do Alkylating agents do?

Answer 1

Cross-link DNA and cause damage

Question 2

What is the common property among chemotherapeutic alkylating agents?

Answer 2

The formation highly reactive carbonium ion intermediates.

Question 3

What atoms in guanine are reactive to alkylating agents?

Answer 3

• N7 (particularly susceptible)
• O6

Question 4

What atoms in adenine ring are reactive to alkylating agents?

Answer 4

• N1 and N3

Question 5

What atoms in cytosine are reactive to alkylating agents?

Answer 5

N3

Question 6

What are the 4 subclasses of Alkylating agents?

Answer 6

• (NNAA)
• Nitrogen Mustards
• Nitrosoureas
• Alkyl Sulphonates
• Atypical

Question 7

What 5 drugs are discussed in the Nitrogen Mustards class:

Answer 7

• MCIMC
• Mecholrethamine
• Cyclophosphamide
• Ifosfamide
• Melphalan
• Chlorambucil

Question 8

What 3 drugs were discussed of the class Nitrosoureas?

Answer 8

• (CSB)
• Carmustine (BCNU)
• Sreptozocin
• Bendamustine

Question 9

What drug is classed as a Alkyl sulphonate?

Answer 9

Busulphan

Question 10

What 3 drugs are considered Atypical alkylating agents?

Answer 10

• (PDT)
• Procarbazine
• Dacarbazine
• Temozolomide

Question 11

What is the MoA of Alkylating Agents

Answer 11

1. Modified guanine can mispair with thymine residues during DNA synthesis, leading to substitution of thymine for cytosine.
2. Alkylation of the N7 creates lability in the imidazole ring, leading to opening of the ring and excision of the damaged guanine residue. Mispairing and imidazole ring opening can lead to attempts to repair the damaged stretch of DNA, causing strand breakage.
3. Cross-linking of two nucleic acid chains
   
   1. Causes major disruption in nucleic acid function.
4. Lethality of DNA alkylation depends on:
   
   1. Recognition of the adduct
   2. Creation of DNA strand breaks by repair enzymes
   3. Intact apoptotic response.

Question 12

What alkylating agents require in vivo activation?

Answer 12

Cyclophosphamide, ifosfamide, dacarbazine.

Question 13

Describe Cyclophosphamide

Answer 13

• Alkylating agent
• Requires in vivo activation
• Metabolite acrolein causes hemorrhagic cystitis, which reacts with the bladder wall.
  
  • Can be prevented by 2-mercaptoethanesulfonate
• Can cause SIADH
• Mainly used for non-hodgkins, ovarian, and breast cancer.

Question 14

What does 2-mercaptoethanesulfonate do? and what is it used in conjunction with?

Answer 14

• Conjugates acrolein in urine
• In conjunction with Cyclophosphamide treatment.

Question 15

What cancer is Melphalan used to treat?

Answer 15

Multiple myeloma

Question 16

What cancer is Chlorambucil used to treat?

Answer 16

Standard for Chronic Lymphocytic Leukemia

Question 17

What is the common symptom following administration of Nitrogen mustards?

Answer 17

Nausea and vomiting

Question 18

What side-effects may occur with Ifosfamide use?

Answer 18

• Altered mental status
• Coma
• Generalized seizures
• Cerebellar ataxia

Question 19

What happens in conjunction with myelosuppression?

Answer 19

Immune suppression

Question 20

What are the side-effects of Busulfan?

Answer 20

• Suppresses all blood elements
  
  • Particularly stem cells
  • Produces a prolonged and cumulative myelosuppression

Question 21

5 Mechanisms of Resistance to Alkylating Agents?

Answer 21

• Decreased Permeation of actively transported drugs
• Increased intracellular glutathione
• Increased activity of DNA repair pathways
• Increased metabolic degradation
• Impaired apoptotic pathways.
  
  • Overexpression of BCL-2

Question 21

5 Mechanisms of Resistance to Alkylating Agents?

Answer 21

• Decreased Permeation of actively transported drugs
• Increased intracellular glutathione
• Increased activity of DNA repair pathways
• Increased metabolic degradation
• Impaired apoptotic pathways.
  
  • Overexpression of BCL-2

Question 22

What are the three platinum coordination complexes?

Answer 22

Cisplatin

Carboplatin

Oxaliplatin