Anti-cancer drugs

Question 1

What are the cytotoxic drug classes (chemotherapy)?

Answer 1

TAMPAC

Topoisomerase inhibitors
Anti-metabolites
Mitotic inhibitors
Platinating drugs
Alkylating drugs
Cytotoxic antibiotics

Question 2

Common chemo side effects

Answer 2

Acute:
Alopecia, mucus membrane ulceration, GI effects- nausea, vomiting, myelosupression
Chronic:
Nephrotoxicity, Pulmonary toxicity, Cardiotoxicity, Neurotoxcity, Haematologic and immunologic impairment, secondary malignancies, teratogenic, premature menopause, infertility, endocrine disruption

TBH, common sense: chemo attacks rapidly proliferating cells in general (can be slow or high growth fraction malignancies)

Question 3

Chemo combinations advantages

Answer 3

1. Maximal cell kill within range of toxicity
2. Synergy
3. Prevent or slow development of resistance

Question 4

Chemo drug principals

Answer 4

1. Diff toxicities so can use both drugs at max dose with minimal lethal effect
2. Optimum scheduling: Shortest time to remission by use at optimal dose and schedule
3. Mechanism of interaction: understand ddi for max effect
4. Avoid dose changes eg lowering drug dose when adding new drug
5. Efficacies: Only drug with single agent efficacy should be combined

Question 5

Alkylating agents

Answer 5

Phase non-specific
MOA: Forms covalent bonds with DNA -> crosslinks DNA, causes breakage in DNA, disrupt DNA replication and transcriptiom
Examples: Nitrogen mustards, ETHYLenimines (Thiotepa), ALKYL sulfonates (Busulfan)

Question 6

Platinating drugs

Answer 6

Phase non-specific
MOA: Forms DNA adducts so cause intrastrand crosslinks, DNA-protein crosslinks
Examples: CisPLATIN (1), carboPLATIN (2), oxaliPLATIN (3)
Excretion exchange via renal route, cisplatin contraindicated in if creatinine levels <60ml/min, carboplatin can be used in mild renal impairment

Question 7

Antimetabolites

Answer 7

Cell-cycle specific
MOA: Interfere with one or more enzymes/ reactions necessary for nucleic acid synthesis, incorporated into DNA and produce stress signals
Methotrexate
MOA: Inhibit dihydrofolate reductase (same as trimethoprim) ->Prevents thymine monophosphate synthesis
5-Fluroracil
MOA: Inhibit thymidylate synthase, misincorporation into DNA/RNA

Question 8

Cytotoxic antibiotics

Answer 8

Phase non-specific
MOA: Inhibit RNA, RNA synthesis, topoisomerase II, alter membrane fluidity and ion transport, creates iron mediated free oxygen radicals that damage DNA and cell membranes
Examples: Doxorubicin, daunorubicin, idarubicin, Mitomycin C, Bleomycin

Question 9

Microtubule inhibitors

Answer 9

Cell-cycle specific
MOA: Bind to beta subunit tubulin, disrupt formation of microtubules, improper attachment of microtubule to kinetochore activate mitotic checkpoint
Examples: Vinca alkaloids- Vinblastine, Vincristine, Vinorelbine (bind to polymerising end, preventing tubule elongation), Alkaloid esters- Paclitaxel, Docepaxel, Cabazitaxel (stabilises microtubule, preventing shortening or depolymerisation)

Question 10

Topoisomeras inhibitors.

Answer 10

Phase non-specific
MOA: Binds to either type I or II topoisomerase, interfering with transcription or DNA replication by disruption of appropriate DNA supercoiling
Examples: Type I (-tecan): Irinotecan, topotecan
Type II (-poside): Amsacrine, etoposide, teniposide

Question 11

Imatinib

Answer 11

BCR-ABL TKI, treats CML

Question 12

Bevacizumab

Answer 12

Block VEGFR, treats some lung adenocarcinoma

Question 13

Trastuzumab

Answer 13

Block HER2, treats HER2 Breast adenocarcinoma

Question 14

Gefitinib (-tinib)

Answer 14

TKI

Question 15

Therapeutic antibodies

Answer 15

Neutralising (Block blood vessel induced by tumours)
Effector-mediated cytotoxicity
Antibody drug conjugates (Brentuximab)

Question 16

T cell immunotherapy

Answer 16

Adoptive cell transfer- patients own T cells engineered to target cancer cells
CAR T cells- T cells engineered to express CARs that recognise tumour cells
Immune checkpoint inhibitors for CTLA-4 and PD1/ PDL1