Cancer Theraputics Flashcards
(27 cards)
How to Alkylating agents work?
React with DNA in all phases of the cell cycle
Provided electron rich atoms that form covalent bonds with DNA molecules that results in cross linking and intrastrand linking. This does not allow topoisomerase and helicase to uncouple the stands of DNA prior to transcription
Types of alkylating agents and some examples of each?
Nitrogen Mustards
- Melphalan
- clorambucil
- cyclophosphamide/ifosfamide
Alkyl Sulfonates
- Busulfan
Nitrosoureas
- Carmustine
Triazenes
- temozolamide
Platinums
- Cisplatin
- Carboplatin
- Oxaliplatin
Alkylating agents toxicities?
BM suppression
Impact on intestinal mucosa
Alopecia
Pulmonary fibrosis
Hepatotoxicity
Gondal Toxicity, teratogenesis
Which Alkylating agents are Vesicants? What is a vesicant?
Alkylating agents with a short half life are vesicants
- nitrosoureas and nitrogen mustards
Vesicants are agents that can cause localized damage at the site of infusion
Which alkylating agents produce Acrolein via the CYP450 pathway? what is the complication of Acrolein?
Cyclophosphamide/ifosfamide are nitrogen mustards that are metabolized to Acrolein via CYP450
Acrolein causes hemorphagic cystitis
What are the toxicities of platinums?
Toxicities of platinums are similar to alkylating agents toxicities because platinums are a form of alkylating agent
- Immunosupression
- GI mucisal upset causing ulcers, dia, nausea and vomiting
- Cation wasting nephropathy (helped with lots of rehydration)
- Peripheral neuroapthy (sensory and motor, may be exacerbated by the cold)
Explain the mechanism of action of antimetabolites?
Work by incorperating DNA base anologues or inhibiting production or restoration of DNA bases
Examples of antimetabolites chemo agents?
5-FU (and the pro drug capecitabine)
Methotrexate
Pemetrexed
Cytarabine
Gemcitabine
6-Mecaptapurine
Cladribine
Antimetabolite side effects?
BM suppression
GI toxicity (Ulcers, dia, nausea, vomiting)
Skin rash (hand and foot, can desquamate in severe cases)
Hepatotoxicity
Arthraliga and myalgias
Explain the mechanism of action of topoisomerase inhibitors?
Toposiomerase untangles (or tangles) up DNA to allow for DNA replication
By inhibiting topoisomerase, the cell cannot undergo mitosis
irinotecan and topotecan, inhibitors of topoisomerase I, and etoposide and teniposide, inhibitors of topoisomerase II
There are two types of topoisomerase inhibitors. What are some examples of each?
Topoisomerase 1 inhibitors:
- Irinotecan, topotecan
Topoisomerase 2 inhibitors:
- Doxorubicin, Epirubicin
- Etoposide, teniposide
- Dactinomycin, mitoxantrone
Topoisomerase inhibitor toxicities?
Vesicants
GI upset (profound diarrhoea)
Secondary melignancy (leukaemia)
Anthracyclines (doxorubicin, epirubicin) - cardiotoxicity (usually HFrEF) and red urine (colour of the drug)
Explain the MoA of Antimicrotubule agents?
Interferes with the microtubules such that alignment or organelles for mitosis is disrupted and cell death occurs
Types of microtubule agents and some examples?
Taxanes:
- Paclitaxel, Docetaxel, Cabazitaxel
Vinca alkyloids
- Vincristine
Toxicities of microtubule agents?
Neuropathy - can be irreversible, usually UL and LL sensory, can be tinitus
Docetaxel can cause capillary leak syndrome mimicking peripheral oedema
Name some broad types of endocrine therapies?
ER and PR suppression with SERMs / aromatase inhibitors
- used in Breast, avarian, and endometrial cancers
Testosterone suppression with GnRH agents or novel hormone antagonists
- Used in Prostate cancer
TSH suppression with thyroxine
- used in thyroid cancer
Somatostain anologues
- Used in NETs
How do targeted therapies work in general?
Cancers cells may be highly dependant on an over expressed onogenic pathways such as the EGFR, KRAS, BRAF, MEK pathway or the HER2+ pathway
This allows for the used of drugs that target this pathway
Higher therapeutic indicies can be achieved due to the relative lack of expression on other cells
Usually -nib (TKIs) and -mabs (monoclonal antibodies) are targeted therapies
-nibs are small molecule TKIs and may get intracellular
-mabs are large molecules and connot get intracellular
What are the two cell targets of immunotherapies?
CTLA-4 inhibibition (older immune checkpoint inhibitors)
PD-1 / PDL-1 inhibition (modern immune checkpoint inhibitors)
Explain the molecular MoA of CTLA-4 inhibitors
MHC peptide complex on APC recognized by TCR
Second signal for T cell activation from CD80/86 to CD28
CTLA-4 is also expressed on T cells, it has much higher affinity for CD80/86 compared to CD28. When present it preferentially binds to CD80/86 causing T cell inactivation
Blockade of CTLA-4 allows CD28 to bind CD80/86 therefore T cell is upregulated
Explain the molecular MoA of PD-1 / PDL-1 inhibitors
PD1 on T cell usually binds PDL1/2 on APC resulting in downregulation of T cell activity
Tumour cells over express PDL1, this results in inhibition of tumor specific effector T cells
Blocking PD1 or PDL1 allows for recognition in the periphery (compared to just recognition in the LN as with CTLA4i)
Does immunotherapy work best against highly mutates cancers, or non highly mutated cancers?
Highly mutated cancers have more neoangigen production allowing more opportunity for Immune system recognition
Immunotherapy toxicities ?
Immune activation results in -itis’s
Almost any body system or organ can be effected
In the event of a severe immune reaction, immunosupression is key as this is an immune driven process. Therefore steroids are primary engagement management
In severe reaction, may need to consider ceasation and other immunosupressive drugs such as infliximab or mycophenylate
Do not cause neutropenias!
What are the organs most commonly affected by immunotherapy toxicities?
Thyroid
- 12% of pts
- treat if symptomatic
- Prednisone PO or methylpred IV in acute setting
- Hypothyroid -> give levothyroxine
- Hyperthyroid -> can use carbimazole if severe, but prednisolone should be sufficient
Colitis
- 5-10% of pts
- Grade 1: <4 stools more than baseline - Rx loperamide
- Grade 2: 4-6 stools more than baseline - w/h immunotherapy, PO or IV steroids with taper when improved
- Grade 3: >7 stools more than baseline - w/h immunotherapy, IV steroids. If refractory over 3-4 days then add infliximab or vedolizumab
- Grade 4 - perforation - permanantly dicontinue immunotherapy. IV steroids. If refractory over 3-4 days then add infliximab or vedolizumab. surgical review
Renal dysfunction
- G1: Cr <1.5x baseline (or ULN) - continue immunotherapy
- G2/3: Cr 1.5-6x baseline (or ULN) - w/h immunotherapy, PO pred. If refractory treat as G4
- G4: Cr >6x baseline (or ULN) - permanantly dicontinue immunotherapy. IV steroids with PO taper
Pneumonitis
- Rare, <1%
- Treat if symptomatic, not just based on radio findings
Explain the MoA of antibody drug conjugates?
Chemotherapy agent attached to antibody. Uses antibody to deliver chemo payload to the area
