Chemotherapy/drugs

Question 1

Antimetabolites: methotrexate (S phase only)

Answer 1

Methotrexate (MTX)
Chemotherapy agent & immunosuppressant
Uses: malignancy (leukemia, lymphoma, breast cancer, lung disease, trophoblastic disease), autoimmune diseases, ectopic pregnancy & medical termination of pregnancy

• *Antimetabolite**
• Competitive inhibitor of DHFR - involved in tetrahydrofolate (THFA) synthesis
• Folic acid required in DNA synthesis, synthesis of base pairs
• Also inhibits purine metabolism (inhibits T cell activation)

Pharmacology
Bioavailability: 60% at low doses, lower at higher doses
Protein binding: 35-50%
Metabolism: hepatic & intracellular
Half life: 3-10hrs (low doses), 8-15hrs (high doses)
Excretion: 80-100% in urine

Key side effects

• Hepatotoxicity
• Mucositis/stomatitis
• Pneumonitis/pulmonary fibrosis
• Teratogenic

Folinic acid
Derivitave of THFA
Used to decrease toxic effects of MTx
Treat overdose
‘Rescue therapy’: enters cell despite active MTX and is converted to THFA involved in DNA synthesis, cell cycle
Reduces hepatotoxicitty, stomatitis & GI complications if administered weekly

Also acts to enhance 5-FU

Question 2

Anthracycline- Doxorubicin/Danorubicin

Answer 2

Doxorubicin (Adriamycin)
Chemotherapy agent
Uses: Hodgkin’s lymphoma/NHL, ALL/AML, Ewing’s, germ cell tumors breast & bladder cancer

• *Anthracycline** class, antitumor antibiotic (interferes with DNA function)
• Inhibits topoisomerase which relaxes DNA coils for transcription
• Prevents DNA replication

Side effects: cardiotoxicity (DCM)- reduced by dexrazoxane, hair loss, mucositis, urine discoloration
- Cardiomyopathy incidence dose dependant (4% low doses, 18% mod doses, >36% high doses)

Pharmacology
Bioavailability 5% (oral)
Protein binding: 75%
Metabolism: hepatic
Half life: triphasic 12,in, 3.3h, 30h (mean 1-3h)
Excretion: 50:50 urine/faeces

Danorubicin-

Question 3

Platinum- cisplatin/carboplatin

Answer 3

Cisplatin
Chemotherapy agent

Uses: lung, brain, bladder, breast, head & neck, oesophageal, testicular, ovarian, cervical & neuroblastoma

• Germ cell tumors
• CNS
• Neuroblastoma

Platinum based anti-tumor class

• Binding to DNA to inhibit DNA replication
• Cell cycle independant

Pharmacology
Bioavailability: 100%
Protein binding: >95%
Half life: 30-100hrs
Excretion: Renal
Cyclophosphamide.

Side effects: BM supression, hearing loss/ototoxicity, nephrotoxicity (proximal tubule), parasthesias/neurotoxicity, electrolyte disturbances, haemolytic anemias
- Amifostine, sodium thiosulfate protective

Carboplatin
- SFx: above + anaphylaxis

Question 4

Vinca Alkaloid (M phase)- Vincristine/vinblastine

Answer 4

• Class: Vinca alkaloid - bind to tubulin and inhibit formation of spindle fibres (microtubules), during mitosis - halt division of cells and cause cell death
• MOA: Inhibits microtubule formation , CYP450 substrate
• Uses: ALL, NHL/HL, Wilms, Ewing’s, neuroblastoma, rhabdomyosarcoma
• Side effects: constipation, neuropathy, jaw pain, alopecia, ptosis, SIADH
• Cause minimal BM suppression (along with steroids, asparaginase, bleomycin)

Vinblastine: LCH, CNS tumors

Question 5

Topoisomerase 2 inhibitors- Etopaside (VP-16)

Answer 5

• Class: Topoisomerase II inhibitors
• MOA: Block topoisomerase function (unwinding DNA), uncoil DNA for replication
• Use: ALL/AML, Ewing’s, germ cell tumors
• Side effects: N&V, myelosupression, secondary leukemia

Question 6

Alkylating agent- Cyclophosphamide

Answer 6

Cyclophosphamide
Cytotoxic agent - used in chemotherapy
DNA alkylating: add alkyl group (eg CH3) to base pair–> disrupt double helix of DNA –> DNA breakage and death, most active in resting phase of cell cycle

Administered IV or orally

MOA in SLE
Immunosupressant
Usually used in lower doses, if not responding to steroids
- Also in other vasculitis GPA, MPA,churg strauss, cryoglobulinemia

Side effects

• BM suppression (WBC >other cell lines, nadir 7-14d into therapy)
• Bladder (hemorrhagic cystitis)
• Infertility (M & F, related to duration of Rx)
• Malignancy (leukemia/lymphoma, bladder ca)

Question 7

Carboplatin

Question 8

Cell cycle - outline the cell cycle and phases implicated by chemotherapy agents

Answer 8

M phase: mitosis

• Vinca alkaloids (vincristine, vinblastine)
• Topoisomerase II inhibitors (etopaside)
• Taxanes/microtubule inhibitors (doxataxel, paclitaxel)

G1: cell growth

• Asparaginase
• Steroids

S phase: DNA synthesis - antimetabolites/topoisomerase 2 inhibitors, prednisolone
- Antimetabolites (methotrexate, 5-Fu, 6-MP, thioguanine, cytarabine), hydroxyurea, prednisolone

G2: cell growth

• Bleomycin
• Irinotecan/topotecan
• Mitotoxantrone

Cell cycle independant: , cisplatin

• Alyklating agents (ciclofosfamide, ifosfamide)
• Platinums (cisplatin, carboplatin)
• Anthracyclines (doxorubicin, duanorubicin)
• Antitumor antibiotics: Bleomycin/actinomycin/mitomycin

Question 9

Antitumor antibiotic: Bleomycin, actinomycin, mitomycin

Answer 9

Bleomycin
Binds to DNA, cleaves DNA strands- G2 phase arrest
Uses: HL/NHL, germ cell tumors

Side effects: pneumonitis, fibrosis, mucocuaneous reactions- stomatitis/palmar lesions

No myelosupression

Dactinomycin:
Inhibits DNA transcription
Wilm’s, Ewing’s & rhabdomyosarcoma
- Mucosal ulceration/tissue necrosis with extravasation, myelosupression

Question 10

Asparaginase

Answer 10

Chemotherapy agent, enzyme in food processing
PEG vs L asparaginase
Uses: ALL - tumor cells unable to make own asparagine, relies on circulating levels
Catalyzes conversion of L-asparagine to aspartic acid/ammonia (decreases available asparagine -> leads to selective tumor cell death)
Side effects: allergic reaction, coagulopathy (decreased clotting factor synthesis/DIC), pancreatitis, cerebral sinus thrombosis, hyperglycemia

Question 11

Cyclosporin - calceneurin inhibitor (immunosupressant post transplant)

Answer 11

Cyclosporin
Calcineurin inhibitor
Immunosuppressant

Uses: Rejection prevention in organ transplants (i.e GVHD), RA, psoriasis, Crohn’s, nephrotic syndrome

MOA: decreases cytokine production from T-cells (forms complex with cyclophillin to block calceneurin)

Metabolism: CYP3A4
Half life: variable, up to 24h
Excretion: hepatic

Side effects

• Gingival enlargement
• Hirstutism
• Peptic ulcers, pancreatitis
• D&V
• Parasthesia

Decreased GFR- increased uric acid retention, hyperkalemia, hypernatremia
Renal vasoconstriction- hypertension
Risk of opportunistic infections
Group 1 carcinogen (evidence in humans)- SCC, non-Hodgkin lymphoma

Question 12

Antimetabolites: Cytarabine (Ara-C), 5-fluorouracil (5-FU), 5-MP

Answer 12

Pyramidine analog- inhibits DNA polymerase
Treatment: leukemia, lymphoma, solid tumors
Side effects: N&V- high emetogenic potential, myelosupression, conjunctivitis/mucositis, cytarabine fevers, leukoencephalopathy (decreasing WM)

Purine analog inhibits purine synthsis
Treatment: leukemia, lymphoma
Side effects: myelosupression, hypoglycemia