Mechanisms of anti-cancer drugs Flashcards

1
Q

What type of drug is methotrexate?

A

Antimetabolite

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2
Q

What type of drug is 5-fluoracil

A

Antimetabolite

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3
Q

What type of drugs are BCNU, CCNU and methyl-CCNU?

A

Chloroethylnitrosureas which are alkylating agents

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4
Q

What type of drugs are chlorambucil, melphalan, mechlorethamine ?

A

Nitrogen mustards which are alkylating agents

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5
Q

What are the three modes of drug induced damage to DNA?

A

1) Covalent binding
2) Intercalation
3) Strand breakage

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6
Q

How can bleomycin be described

A

A radiomimetic drug

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7
Q

How do the majority of alkylating agents get taken up into cells

A

Non-specifically and passively

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8
Q

How is mechloroethamine taken up into cells

A

Due to its chemical similarity to choline it uses a choline transporter

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9
Q

How do cancers become resistant to mechloroethamine treatment?

A

Mutations in the choline transporter required for its uptake into cells

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10
Q

How is melphalan taken up into cells

A

Due to its chemical similarity to leucine/ other neutral amino acids; it’s actively transported into cells.

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11
Q

How do nitrogen mustards produce interstrand crosslinks on DNA

A

1) Random loss of a chlorine ion forms a positively charged intermediate which binds to the N7 on guanine. Same happens on the second arm of the nitrogen mustard which forms a bond with another N7 guanine on the other DNA strand creating an interstrand crosslink between the two strands.

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12
Q

Why does the major product of nitrogen mustards not produce a DNA interstrand crosslink?

A

Because both arms of the nitrogen mustard don’t react with DNA. One might react with an OH group instead which would produce a monofunctional, non-toxic adduct.

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13
Q

Why are chloroethylnitrosureas effective in mouse models compared to human cancers?

A

When chloroethylnitrosureas are metabolised they produce chloroethyl, a positively charged monoadduct which can adduct to N3 adenine, N7 guanine or O6 guanine. If it binds to O6 guanine then it goes on to form an interstrand crosslink. In mice, O6 methyltransferase is incapable of repairing the chloroethyl monoadduct as it is a highly specific enzyme. In humans it acts as a broader alkyltransferase so is able to repair chloroethyl guanine monoadducts before a crosslink is made. Therefore, it is not cytotoxic to cancer cells.

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14
Q

Why is treatment with BCNU, CCNU and methylCCNU effective in around one third of gliomas?

A

In these cancers, there is a loss of O6-methyltransferase expression. Therefore, the chloroethyl O6 guanine monoadduct is not repaired and goes on to produce an interstrand crosslink, becoming cytotoxic to the cell.

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15
Q

How do platinum drugs induce a cytotoxic effect in cancer cells

A

Have bifunctional Chlorine arms which form reactive intermediates. These react with OH and form a co-ordination complex that ultimately is able to produce mono/bifunctional adducts which are cytotoxic to the cancer cell.

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16
Q

How do intercalating agents induce a cytotoxic effect to cancer cells.

A

In the presence of an intercalating agent; topoisomerase will bind to the first strand of DNA, and the second, but blocks the DSB formation and passing through of the second strand of DNA. As a result, a ternary structure is formed (DNA, drug and enzyme). This is a cleavable complex which stops replication and becomes cytotoxic to the cell.

17
Q

Why is cisplatin highly effective in the treatment of testicular cancer Vs others such as bladder cancer.

A

The bulky adduct produced by cisplatin is repaired via NER. In testicular cancer cells, XPA protein is missing (required for NER) so the bulky adduct is not repaired and becomes cytotoxic to cancer cells and not normal cells.

18
Q

Why is multiple myeloma initially so sensitive to melphalan?

A

Melphalan is an alkylating agent that creates interstrand crosslinks that are cytotoxic to cells.

19
Q

Patients treated with melphalan almost always relapse and are resistant to melphalan treatment subsequently. Why is this the case?

A

Resistant cells have acquired the ability to repair crosslinks, shown as an increase in the unhooking of crosslinks in treated Vs naive patients.

20
Q

How do ovarian cancer patients become resistant to cisplatin treatment?

A

Treated patients gain the ability to repair interstrand crosslinks in cancer cells, so no longer respond to cisplatin.

21
Q

What happens to DNA repair in normal cells in young Vs old people and what does this suggest about tolerance of certain therapies in young populations?

A

Ability to repair damage decreases in normal cells with age. Cytotoxic chemotherapy is therefore more tolerated in younger patients as their normal cells can repair compared to older patients.

22
Q

How does cisplatin treated in combination with gemcitabine overcome cisplatin resistance in ovarian cancer

A

The addition of the antimetabolite prevents the repair of DNA crosslinks produced by cisplatin (the mode of resistance), creating a synergistic effect

23
Q

In what order does gefitinin and cisplatin treatment need to be given and why?

A

Cisplatin to induce DNA damage, followed by gefitinib to inhibit EGFR pathway and prevent DNA repair of cisplatin induced damage.

24
Q

What is a good molecule that binds specifically to DNA

A

PBD

25
Q

How can monomeric PBD be made into a bifunctional adduct?

A

Artificially made into a dimer.

26
Q

Why is PBD dimer induced interstrand crosslinking persistent compared to the crosslinking produced by other drugs such as melphalan

A

PBD doesn’t change the structure of DNA when it produces crosslinks. Melphalan produces kinks in the DNA and is recognised by repair pathways, removing crosslinks.

27
Q

Why is the valine-alanine linker in an ADC so important?

A

needs to be stable, so when in the blood it doesn’t release the drug causing off target toxicity. It needs to be able to be cleaved in the lysosome, releasing the drug into the cell