DNA-interactive cancer agents - Cross-linking agents Flashcards
How do cross-linking agents work
Contain two alkylating moieties separated by various distances by linkers. They alkylate two nucleophilic functional groups either on the same or opposite strands of DNA. Adducts formed represent either an ‘intrastrand’ or ‘interstrand’ cross-link.
how do Nitrogen Mustards work?
Molecules ‘staple’ the two strands of DNA via covalent interactions in the major groove and block replication. Also demonstrates that RNA polymerase is blocked by mustard-DNA adducts.
What is the basis of selectivity in Nitrogen mustard agents?
- Kinetic: kills faster growing cells
- Cancer cells are less proficient at repairing mustard adducts compared to healthy cells
G-C rich transcription factors binding sites
G-C rich sequences in DNA eg: Burkitt’s lymphoma
What are the mechanism or cancer resistance to nitrogen mustards
- MDR-related resistance through upregulation of p-glycoproteins
- Increase in [glutathione] in tumor cells: glutathione forms adducts with mustards which are no longer electrophilic and unable to react with DNA
- Cancer cells become resistant to nitrogen mustards by up regulating repair processes
Give an example of an aliphatic nitrogen mustard and state its mechanism of action in clinical use
Chlormethine. It undergoes initial interal cyclization through elimination of chloride to form a cyclic aziridinium ion. Chlormethine can give rise to interstrand cross-link (locks the two strands of DNA together).
What is Chlormethine indicated for? whats a key side effect?
Management of Hodgekin’s disease - vomiting
Characteristics of Aromatic Nitrogen Mustards?
Aromatic:
- Milder alkylating agents than aliphatic
- Aromatic ring acts an electron sink withdrawing e- from Nitrogen atom (not sufficiently basic to cyclize) and discouraging formation of aziridinium ion formation. Alkylation resembling an SN1 process.
- Sufficiently deactivated to reach their target DNA site before being degraded by reacting with collateral nucleophiles => ORAL DELIVERY
Give an example of a nitrogen aromatic mustard, and what it is used to treat.
Melphalan. Contains carboxyl group + an amino acid residue (phenylalanine) which increases selectivity. Used to treat myeloma and occasionally solid tumors (breast, ovarian) and lymphomas
Example of a conjugated nitrogen mustard
Estracyt - A combination of estrogen and Chlormethine joined through a carbamate linkage.
- Carbamate linkage is cleaved by plasma and/or cellular carbamases allowing the two components to act at their different sites.
- Oestrogen alone: serious CV side effects but attractive for treatment of prostate cancer
- Ecstracyst works to:
- Lower LH (and therefore testosterone levels)
- Block 5-a-reductase (conversion of testosterone to ditestosterone)
- Increase [sex hormone-binding globulin] hence preventing free testosterone from attaching to prostate cancer cells
- Cytotoxic effect on prostate cancer cells
Name a nitrogen mustard cross linking agent that is a platinum complex
Cisplatin. Gven IV and requires intensive IV hydration.
Chemical role:
- Forms intrastrand cross links in the major groove of DNA specifically at:
- (guanine N7)-(guanine N7) adjacent bases
- (guanine N7)-(adenine N7) adjacent bases
Biological role:
- In some cisplatin resistant cell lines, the adducts are rapidly repaired as enzymes can recognize the distortion
What is cis-platin indicated for? and what problems are associated with Cisplatin
Treatment of metastatic germ cell cancers, other tumors
Side effects
- Bone marrow suppression
- GI distrubances
- Hair loss
- Peripheral neuropathy
- Ototixicity
- Nephrotoxicity (monito renal function)
Problem: High cost: Platinum content
indication for Carboplatin. Which is better. Carboplatin or Cisplatin?
Treatment of advanced ovarian cancer and lung cancer. It is better tolderated in terms of side effects
