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Therapeutic Agents > Chemotherapeutics > Flashcards

Chemotherapeutics Flashcards

1
Q

What is cancer?

A

Collection of over 100 diseases caused by abnormalities in a patient’s genetic material. It is the second biggest cause of death globally after cardiovascular disease.

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2
Q

What is the difference between cancer abnormalities in genetic material versus normal genetic material abnormalities?

A

Abnormalities occurring in genetic material can be relatively frequent event in human physiology and may not be harmful. However, cancer occurs when these abnormality is replicate and lead to rapid cell growth.

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3
Q

What is metastases?

A

It is the cause of death in most cancer patients and therefore early diagnosis is critical

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4
Q

What is a tumour and how can it cause problems?

A

A tumour is the uncontrolled growth which causes the lump to form. If it’s not treated, it can cause problems such as spreading into normal tissues nearby, spreading to other parts of the body through your bloodstream, this can cause damage parts of your body such as your organs.

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5
Q

How is cancer treated?

A

If court early enough surgery, this can be in combination with radiotherapy and therapy cancer drugs are also used.

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6
Q

Why does chemotherapy side-effects occur?

A

Chemotherapy inhibits rapid cell proliferation, there’s not only has a result on cancer cells but also other cells such as hair follicles and cells are in the epithelium of the gut

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7
Q

What are new targets for cancer research?

A

As cancer exist due to faults in the DNA called mutation this can cause deregulated protein production, these proteins can be used as new targets for cancer drug discovery

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8
Q

In addition to chemotherapy, what other drug types are being developed?

A

Molecular targeted drugs such as small molecules and biotherapeutics

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9
Q

What scientist are needed for the research of new cancer drugs?

A

Biologist chemist and clinicians in hospitals

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10
Q

What is Akt?

A

Protein found inside the cell, it said signals to the cell nucleus to grow and divide. It’s found over activated in several cancers, including breast ovarian and prostate cancer.

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11
Q

What is a AZD5363?

A

A drug against AKT, which is now in phase 2 clinical trials worldwide with Astrazeneca for breast cancer

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12
Q

What are the ongoing research questions in the laboratory for the drug AZD5363?

A

Can we predict mechanisms of drug resistance early on?

Can we identify ways to overcome this resistance?

Through this research, can we identify new cancer drug targets?

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13
Q

Apoptosis

A

The process of programed cell death

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14
Q

Cell cycle

A

The process of cell division

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15
Q

Chromosome

A

Found in the nucleus of most living cells contains DNA wrapped around histone proteins

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16
Q

Epoxide

A

Free membered ring containing one oxygen and two carbon atoms highly reactive

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17
Q

Gene

A

Distinct sequence of nucleotides forming part of the chromosome

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18
Q

Nucleoside

A

Compound consistent of a purine of pyrimidine base linked to a sugar

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19
Q

Nucleotide

A

Compound consistent of a nucleotide linked to a phosphate group

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20
Q

Oncogenes

A

A gene that can transform a normal cell into a tumour cell

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21
Q

Point mutation

A

Mutation of one or just a few nucleotides in a gene

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22
Q

Suppressor genes

A

Genes that slow down cell division

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23
Q

Topoisomerases

A

Enzymes that catalyse the winding and unwinding and dna strands

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24
Q

What is aflatoxin?

A

The mould that can be found of plants particularly peanuts and corns. If ingested it can be oxidised by the metabolic enzyme CYP450 resulting in a highly strained free membered epoxide ring. It can open easily reacting with guanine base pairs in the DNA.

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25
Q

What is one commonality between the different cells of the human body?

A

Their ability to regulate proliferation

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26
Q

What cells divide divide all the time?

A

Skin cells or members of the Gi tract

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27
Q

What cells divide when they receive appropriate signals from their extra cellular environment?

A

Liver cells, hemopoietic lineages

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28
Q

What cells have the ability to divide but do not?

A

Members of our cardiac lineage, neuronal lineages

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29
Q

What regulates proliferation?

A

Proliferative go signals, anti proliferative stop signals, these are lost by cancer cells

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30
Q

In the cell cycle, what is the responsive phase?

A

The cells respond to intracellular and extracellular cues and decides whether to divide or not.

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31
Q

In a normal cell cycle, what is the autonomous phase?

A

The cell only responds to internal cues, DNA damage and mitotic errors

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32
Q

Loss of proliferative control

A

Leads to cancer

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33
Q

Loss of checkpoints in the cell cycle

A

Cancer progression

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34
Q

What are the two types of chemotherapy drugs?

A

Drugs that act directly on existing DNA such as alkylating/methylating agents, intercalating agents and chain cleaning agents
Or
Drugs are inhibit the synthesis of DNA such as antimetabolites or enzyme inhibitors.

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35
Q

For the evolution of chemotherapy, what happened in the 1940s?

A

Mustard was observed to shrinkers in cancer patients, it was observed in soldiers who had been exposed to mustard gas in the war.

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36
Q

For the evolution of chemotherapy, what happened in the nineteen fifties to sixties?

A

Alkylating agents and antimetabolites were developed

37
Q

For the evolution of chemotherapy what happened in the 1970s?

A

Medical oncology rapidly developed in the 1970s. New cases of compounds were developed such as Anthraccyclines and platinum agents and effective combination therapies.

38
Q

For the evolution of chemotherapy what happens in the 1980s?

A

Increasingly toxic chemotherapeutics developed with no huge advancements and treatment development of topoisomerase inhibitors

39
Q

For the evolution of chemotherapy, what happens in the 1990s?

A

There was increased focus on understanding genetics. The human genome project started and antiangiogenic therapies discovered, drugs that restrict blood vessels to tumours

40
Q

For the evolution of chemotherapy, what happened in the 2000s?

A

A modern focus on targeted therapies

41
Q

What is an alkylating agent?

A

These can be defined as compounds capable of covalently binding an alkyl group carbon chain to a biome molecule such as DNA under physiological conditions. By binding to the DNA the agents disrupt the DNA function and replication process which ultimately lead to sell death these agents are crude binding non-specifically to any DNA strand which can cause extreme side-effects. Also the normal hydrogen bonding of those base pairs.

42
Q

Monoalkylation

A

Only one DNA base is alkylated this inhibiting its ability to form a hydrogen bond with another base pair

43
Q

InterStrand cross linkage

A

Alkylating faces on opposite ends of DNA causing a bridge. This prevent a separation of DNA strand upon replication this terminating the sales division.

44
Q

Intrastand cross linkage

A

Alkylating two bases on the same strand of DNA causing a bridge and preventing its ability to form hydrogen bond with another base pair

45
Q

What are the chemotherapeutic and cytotoxic effects of alkylated agents related to alkylating agents?

A

Directly related to the alkylation of reactive amine oxygen or phosphate groups on DNA.

46
Q

The most important reaction of alkylating agents.

A

With DNA nucleobases, the preferred base is guanine and alkylation usually occurs at the n7 position on guanine

47
Q

Side effects of mustard gas

A

A chemical weapon, caused leukopenia ( decreased white blood cells), damage to bone marrow and lymphoid tissue. However, it shrank cancerous tumours.

48
Q

Why couldn’t mustard gas be used as cancer treatment?

A

It proved efficacious against leukaemia however it was too toxic

49
Q

When are alkyl chloride reactive?

A

They are not reactive under physiological conditions. However with the presence of an electron-rich group such as nitrogen or sulfur it cleaves the alkyl cl bond resulting in a three membered ring. The ring is extremely reactive, which react with dna bases and causes if dna cross linkage.

50
Q

What is chlorambucil?

A

A chemotherapy agent used for the management of chronic lymphocytic leukaemia and malignant lymphomas. It is used as a antineoplastic agent for the treatment of various malignant and non-malignant diseases. It is less toxic than other nitrogen mustards.

51
Q

What is Chlorambucil used to treat?

A

Chlorambucil is an effective treatment for chronic lymphocytic leukaemia and non-Hodgkin lymphoma and still used today. Nearly two thirds of non-Hodgkin lymphoma patients survive over 10 years due, in part to this chemotherapeutic agent.

52
Q

The chemical difference of mustard gas over chlororambucil or chlormethine

A

2 chloroethyl groups directly attached to a sulfur atom, more reactive and poor stability/ selectivity.

53
Q

The chemical difference of chlormethine over chlororambucil and mustard gas

A

It replaces the sulfur with a nitrogen, giving an alkylating nitrogen mustard. More stable then mustard gas

54
Q

The chemical difference of chlororambucil over chlormethine and mustard gas

A

It introduces a phenyl ring, connecting one chloroethyl group through a nitrogen and the other through a methylene carbon.

55
Q

Melphalan

A

Another bifunctional alkylating agent that belongs to the class of nitrogen mustards. Similar to chlorambucil, it consists of an aromatic ring system and an alkylating group. However, melphalan has been further modified to improve its stability and selectivity.

56
Q

How often are platinum drugs used?

A

Platinum drugs are used to treat over 50% of all cancer patients.

57
Q

What is the most frequently prescribed drug?

A

Cisplatin

58
Q

What is a feature of mustard alkylating agents?

A

2 chloride groups

59
Q

How is the mechanism of action for mustard agents similar to that of platinum drugs?

A

The chlorides are cleaved, allowing the molecule to cross-link a DNA base pair

60
Q

Where has cisplatin shown significant efficacy?

A

Against testicular cancer, which 96% of men now survive

61
Q

Phenanthriplatin

A

A potential new cancer treatment, developed by MIT hit the headlines with 40-100 times more efficacy than cisplatin in mice.

62
Q

DNA synthesis inhibitors

A

A class of chemotherapeutic agents that specifically interfere with the process of DNA synthesis during cell replication. These drugs target different aspects of DNA replication, such as enzymes involved in nucleotide synthesis, DNA chain elongation, and unwinding of the DNA helix.

63
Q

Antimetabolites:

A

Folate antagonists
Purine analogues
Pyrimidine analogues

64
Q

Topoisomerase inhibitors:

A

Topoisomerase I inhibitors Topoisomerase II inhibitors

65
Q

Different types of DNA synthesis inhibitors

A

Antimetabolites, Topoisomerase inhibitors, DNA polymerase inhibitors, Helicase inhibitors

66
Q

Folate antagonists

A

(e.g., methotrexate): These drugs inhibit dihydrofolate reductase, an enzyme essential for the synthesis of purines and pyrimidines (DNA building blocks). This inhibition disrupts DNA and RNA synthesis, leading to cell death.

67
Q

Purine analogues

A

(e.g., 6-mercaptopurine, fludarabine): These compounds mimic purine nucleotides and incorporate into DNA and RNA during replication and transcription, resulting in the formation of faulty nucleic acids and cell death.

68
Q

Pyrimidine analogues

A

(e.g., 5-fluorouracil, cytarabine): These agents resemble pyrimidine nucleotides and interfere with DNA synthesis by incorporating into the growing DNA chain, inhibiting DNA replication and transcription.

69
Q

Topoisomerase I inhibitors

A

(e.g., topotecan, irinotecan): These drugs stabilize the cleavage complex formed between topoisomerase I and DNA, preventing the enzyme from rejoining the DNA strand. This leads to the accumulation of single-strand breaks in DNA, which can cause double-strand breaks and cell death when the replication fork encounters the single-strand breaks.

70
Q

Topoisomerase II inhibitors

A

(e.g., etoposide, doxorubicin): These agents stabilize the cleavage complex formed between topoisomerase II and DNA, resulting in the accumulation of double-strand breaks in DNA and subsequent cell death

71
Q

DNA polymerase inhibitors

A

(e.g., aphidicolin)
These compounds inhibit DNA polymerase, the enzyme responsible for synthesizing new DNA strands during replication. By inhibiting DNA polymerase, they directly prevent DNA synthesis and can lead to cell death.

72
Q

Helicase inhibitors

A

(e.g., berberine)
These drugs target helicases, which are enzymes that unwind the DNA double helix during replication. By inhibiting helicases, they hinder the unwinding of DNA, leading to the disruption of DNA replication and cell death

73
Q

methotrexate

A

The main folate antagonist in cancer chemotherapy. Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division. The main action of the folate antagonists is to interfere with thymidylate synthesis by binding to the Dihydrofolate reductase (DHFR) enzyme . Folates consist of three elements: a pteridine ring, p-aminobenzoic acid and glutamic acid;

74
Q

5-FU/ Fluorouracil

A

an analogue of uracil, also interferes with 2′-deoxythymidylate (dTMP) synthesis. It is converted into a ‘fraudulent’ nucleotide, fluorodeoxyuridine monophosphate (FdUMP). This interacts with thymidylate synthetase but cannot be converted into DTMP. The result is inhibition of DNA but not RNA or protein synthesis. It
is a widely used chemotherapeutic and listed as one of the WHO’s essential medicines. It is commonly used to treat colorectal and skin cancer.

75
Q

Prodrugs

A

Ftorafyr and doxifluridine are prodrugs of 5-FU. A prodrug is a molecule that after administration is metabolised leaving the active species. It can be thought of as a shield, protecting the efficacious agent, until it reaches the site of action. Prodrugs are often used to improve a drugs absorption (usually by adding lipophilicity) or protect it from rapid metabolism.

76
Q

Topoisomerases

A

Topoisomerases are enzymes that play a crucial role in managing DNA topology, i.e., the spatial organization of DNA molecules inside the cell. They are responsible for untangling DNA strands, relieving supercoiling, and ensuring proper DNA replication and transcription.

77
Q

Type I topoisomerases:

A

These enzymes work by transiently breaking a single strand of the DNA double helix, allowing the other strand to rotate and relieve the supercoiling. Afterward, they reseal the broken strand.

78
Q

Type II topoisomerases:

A

These enzymes transiently break both strands of the DNA double helix, allowing another double-stranded DNA segment to pass through the break. This process is essential for untangling intertwined DNA molecules, particularly during replication. Type II topoisomerases are further classified into two subtypes: Topoisomerase IIα and Topoisomerase IIβ.

79
Q

The two types of topoisomerase inhibitors

A

topoisomerase poisons (they target type 1) and catalytic inhibitors (they target type 2).

80
Q

The Limitations of topoisomerase inhibitors

A

They can also harm healthy cells, leading to various side effects such as bone marrow suppression, gastrointestinal issues, and cardiotoxicity.

Moreover, cancer cells can develop resistance to topoisomerase inhibitors by overexpressing the target enzyme, altering the enzyme’s structure, or increasing efflux pump activity to expel the drug from the cell. Therefore, there is ongoing research to develop new topoisomerase inhibitors with improved selectivity and reduced side effects.

81
Q

Anthracyclines

A

eg. Dactinomycin target Topo II.

82
Q

Camptothecins

A

eg. Topotecan (marketed in 1996) target Topo

83
Q

Intercalation

A

The process by which compounds containing planar heteroaromatic ring systems are inserted between adjacent DNA base pairs. The molecules sit perpendicular to the axis of the helix without disturbing the hydrogen bonding. Intercalation can cause the unwinding of the DNA strands. Furthermore, the presence of a DNA intercalating agent can inhibit the interaction between DNA and topoisomerase: an enzyme that catalyses DNA winding.

84
Q

Anthracyclines

A

A class of chemotherapeutics that have been extracted from streptomyces bacterium. The compounds are characterised by their very flat aromatic ring structures, such as doxorubicin.

85
Q

Doxorubicin

A

It functions as both a DNA synthesis inhibitor and a DNA intercalator.
As a DNA synthesis inhibitor, it blocks the activity of topoisomerase II, an enzyme involved in DNA replication. By inhibiting topoisomerase II, it prevents DNA from being replicated and cells from dividing.
As a DNA intercalator, it inserts itself between the base pairs of DNA, causing the DNA strands to become kinked or distorted. This intercalation disrupts the normal structure and function of DNA, ultimately leading to cell death.
The dual action of both a DNA synthesis inhibitor and a DNA intercalator makes it an effective chemotherapy agent for treating a variety of cancers.

86
Q

This interference with from doxorubicin DNA structure has several consequences:

A

Inhibition of DNA replication and
Inhibition of transcription

87
Q

Dactinomycin

A

It also known as actinomycin D, is a type of chemotherapy drug that is used to treat various types of cancer, including childhood cancers such as Wilms’ tumor and rhabdomyosarcoma, and certain types of solid tumors and cancers of the testes, cervix, and uterus.

88
Q

Cardiotoxicity

A

The main issue with DNA intercalators is their cardiotoxicity, which often manifests itself 10-20 years after treatment.

89
Q

DNA intercalating agents vs. DNA synthesis inhibitors

A

DNA intercalating agents vs. DNA synthesis inhibitors
DNA intercalating agents are not considered DNA synthesis inhibitors in the strictest sense because their primary mechanism of action is different.
DNA synthesis inhibitors specifically target proteins or processes directly involved in the synthesis of DNA, whereas DNA intercalating agents insert themselves between the base pairs of the DNA double helix, causing structural distortions and interfering with several cellular processes such as replication, transcription, and DNA repair. However, the consequences of their interaction with DNA can indirectly affect DNA synthesis.
While DNA intercalating agents can disrupt DNA replication by causing conformational changes to the DNA helix, their primary mechanism of action is the interference with DNA structure and function rather than directly inhibiting enzymes or pathways involved in DNA synthesis. That being said, the end result of both DNA intercalating agents and DNA synthesis inhibitors is the disruption of normal cellular processes, DNA damage, and ultimately cell death, particularly in rapidly dividing cells like cancer cells.
It is important to recognize that the boundary between these classes may be blurred, as some intercalating agents may indirectly impact DNA synthesis, and some DNA synthesis inhibitors may interact with DNA structure or function.
For example, Doxorubicin is one of the two first isolated and introduced anthracyclines as antitumor agents. It works through two mechanisms of action; 1) intercalates into the DNA double helix without covalent binding, and 2) binds covalently to topoisomerase II (involved in DNA replication and transcription), poisons the cleavable complex of DNA and prevent its re-ligation, and finally results in an apoptotic action.

Therapeutic Agents (7 decks)

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