Module 5.1.1 (Part 1 --> Non-Targeted Antineoplastic Drugs) Flashcards
For non targeted drugs;
A) What are examples of alkylating agents and other antimetabolites?
B) What are examples of natural drugs?
A)
- Alkylating agents: Nitrogen mustards; Alkyl Sulfonates; Nitrosoureas
- Antimetabolites: Folic acid, nucleic acid analogues
B)
- Vinca alkaloids; Epipodophyllotoxins, Antibiotics
- Enzymes, Biological Response Modifiers
What are the general toxicity/adverse effects associated with non-targeted therapy? Provide THREE.
Myelosuppression
- reduction of circulating functional blood cells
- leucocytes, thrombocytes, erythrocytes
- Erythrocytes have longest life (120 days)
Mucositis (evident within 5-7 days more rapid then myelosuppression)
- destruction of gastrointestinal lining
- mouth/oesophagus (most sensitive) –> reduce intake
> irritation ulceration infection dehydration pain poor nutrition dysphagia
- small/Large intestine –> fluid loss
> diarrhoea haemorrhage cramping pain malabsorption infections dehydration
Alopecia (hair loss) & Hyperuricaemia (lysis of cells)
Teratogenicity
What are the examples of nitrogen mustards? Include their MOA.
- Cyclophosphamide / Ifosfamide (MOA in 3.2.1)
- Chlorambucil (oral)
> Bis-(2-chloroethyl group) key to activity (Bifunctional) –> alkylate DNA
> less cytotoxicity than cyclophosphamide
> CLL, lymphomas, breast cancer
> ADEC cat D and may cause seizures
What is the MOA of dacarbazine (alkylating agent)? Which cancers is it used in? Adverse effects?
MOA (injection only)
- Analogue of step 8 purine de-novo –> block at G2
- Alkylating agent, guanine affected (binds to DNA and block its effects)
- Pro drug
- active metabolite = methyltriazenoimidazole carboxamide (MTIC) –> metabolites in urine
Useful in melanoma and Hodgkins disease
AE
- Neutropenia, thrombocytopenia (late). Pain from injected vein, flu syndrome, facial flushing.
Why do children clear busulfan (alkylating agent) faster than adults? Which cancer is it used in? Adverse effects?
- Children 2-4x faster clearance compared to adult –> completely metabolised –> children require higher dose
Cancer used in: Main CML (chronic myeloid leukaemia) treatment before GLIVEC (Imatinib)
Adverse effects
- hyperpigmentation, potential irreversible decreased bone marrow, weight loss, seizures (may need antiepileptics), tachycardia pulmonary fibrosis
- myelosuppression main side effect
For cisplatin (platnium complexes);
A) What are some other types of platinum complexes
B) What cancer is it used for?
C) MOA?
D) Toxicity?
E) Main AE
A) slow IV
- Carboplatin and Oxaliplatin
B)
- testicular, ovarian, bladder, head/neck/lung , colorectal cancers
C)
- Activates intracellularly (low Cl- )
- DNA binding (intra & inter strand cross-links)
- guanine sensitive
D)
- reduction of Ca2+,Mg2+,K+,PO4 –> give fluid
- Kidney (acute tubular necrosis) : seizures
- Myelosuppression – also hearing loss, allergic reactions
E)
- VERY EMETIC
- Cisplatin the most emetic –> use anti-emetic drugs (5 HT-3 blockers the best)
For 5-FU antimetabolites;
A) What is the MOA
B) What are they used for?
C) AE?
D) How is it given?
E) Interactions?
F) What can be lethal?
A)
- inhibit synth pyrimidine nucleotides
- 5-fluorouracil (5-FU) –> locks thymidylate synthase in inhibited state (5- FdUMP) –> faulty mRNA formation or DNA strand breakage
B)
- Acute myelocytic leukaemia
- Colon, rectum, breast cancer & others
C)
- GIT epithelial damage (NVD)
- myelosuppression
- Hand-Foot syndrome
- Angina-like chest pain - (coronary vasospasm)
- alopecia
D)
- Given either bolus I.V. or infusion or cream-skin
E)
- Cisplatin: DNA strand breaks; thymidylate synth inhibtor
- Methotrexate: Increased RNA incorporation via increased PRPP pools. decreased purine synhesis
- Metronidazole: decrease clearance of 5-FU, increased toxitity
- Leucovorin: increasd cytotoxic effect (colorectal / gastric cancer)
F)
- Dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal
- 5-FU is metabolised by DPD
What is a produg of 5-FU? What is the MOA and AE?
Capecitabine
- Thymidine phosphorylase then hydrolyzes 5’-DFUR to the active drug 5-FU
AE = as per 5-FU
What are the THREE other examples of other pyrimidine analogues? What is the MOA?
- Cytarabine (Ara-C)
- treated like deoxy-riboside, converted to triphosphate
- competes for space in DNA with dCTP; +DNA polymerase
- blocks elongation & temple function: S phase specific
- Gemcitabine
- Analogue of deoxy-cytidine
- Infused IV over 30min
- Metabolised & renal excreted
-
Azacitidine (s.c or i.v.)
* Hypomethylation of cytosine in DNA (restricts & modifies gene expression + mismatch error correction)
What are examples of Vinca alkaloids? What is their MOA? What is their AE?
Vinblastine(VBL), Vincristine(VX), Vinorelbine(VRB)
MOA
- Bind to tubulin
- Mitotic spindle - cells kept in metaphase - apoptosis
- IV only
Vincristine used for haematologic neoplasms
AE
- periph neurological (VX) – ANS, ear, hyperuricaemia
- Severe myelosuppression (except VX)
> CYP3A metabolised: P-gp substrates
What are examples of taxanes? What is their MOA? Why are they used?
Paclitaxel (Anzatax) and Docetaxel (Taxotere)
MOA
- Promotes microtubule formation –> stops disassembly
- Metabolised via 3A4 & 2C8
AE
- P-gp substrate (peripheral neuropathy) - sensory
- Toxicity mainly bone marrow – neutropenia, anaemia
- Hypersensitivity, fluid retention, increase in liver enzymes, bradycardia, taste disturbances, pigmentation changes to nails, lacrimal duct obstruction (increased tears)
What are examples of Epipodophyllotoxins? What is the MOA? Uses? AE?
Etoposide
- ternary complex - topoisomerase II & DNA –> breaks double-stranded DNA
- Allows splitting but no rejoining
Uses
- AML, lymphoma, lung, ovarian, testicular carcinoma
AE
Dose limited myelosuppression
- Alopecia, taste alterations, N, V. anorexia, mucositis
- May develop secondary AML as adverse effect
For antibiotics;
A) What is the MOA of dactinomycin? What is it used for? AE?
B) Why is Dauno,doxo,ida,epi (rubicin) used? MOA? AE?
C) Why is bleomycines used? MOA? Activated by?
A)
MOA
- Bind double strand DNA –> cytotoxic – inhibits RNA polymerase
- Topoisomerase II induced DNA strand breakage
- P-gp substrate, no CNS entry
Uses
- IV use, usually in combo with; vincristine for Wilm’ tumour
- Combo with methotrexae for choriocarcinoma
AE
- Myelosuppression, white cells & platelets NVD, stomatitis, alopecia, extravasation
B)
Uses
- ALL, AML, solid tumours
MOA
- interferes with Topoisomerase II (repair)
- Free radical production
- Intercalating agents
> P-gp substrates (drugs work really well if cells dont increase their P-gp, this stops drug geting in)
AE
- cardiomyopathy- sarcoplasmic
- extravasation –> possible necrosis
C)
Uses
- squamous carcinomas of head, neck, lung, lymphomas, testicular tumours
- Low myelo & immuno- suppression
MOA:
- Chelates Fe2+ - then binds DNA- cuts strands
Activated by
- O2 or reducing agents –> keep pure 02 away from lungs
IV infusion –> poor BBB transport –> high levels in skin/lungs
