Procarbazine

Procarbazine is a chemotherapy medication used for the treatment of Hodgkin's lymphoma and brain cancers.[1] For Hodgkin's it is often used together with chlormethine, vincristine, and prednisone while for brain cancers such as glioblastoma multiforme it is used with lomustine and vincristine.[1] It is typically taken by mouth.[1]

Procarbazine
Clinical data
Trade namesMatulane, Natulan, Indicarb, others
AHFS/Drugs.comMonograph
MedlinePlusa682094
Pregnancy
category
  • AU: D
Routes of
administration		By mouth (gel capsule), intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolismliver, kidney
Elimination half-life10 minutes
Excretionkidney
Identifiers
  • N-Isopropyl-4-[(2-methylhydrazino)methyl]benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.010.531
Chemical and physical data
FormulaC12H19N3O
Molar mass221.304 g·mol−1
3D model (JSmol)
  • O=C(c1ccc(cc1)CNNC)NC(C)C
  • InChI=1S/C12H19N3O/c1-9(2)15-12(16)11-6-4-10(5-7-11)8-14-13-3/h4-7,9,13-14H,8H2,1-3H3,(H,15,16) checkY
  • Key:CPTBDICYNRMXFX-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Common side effect include low blood cell counts and vomiting.[1] Other side effects include tiredness and depression.[2][3] It is not recommended in people with severe liver or kidney problems.[4] Use in pregnancy is known to harm the baby.[1] Procarbazine is in the alkylating agents family of medication.[1] How it works is not clearly known.[1]

Procarbazine was approved for medical use in the United States in 1969.[1] It is on the World Health Organization's List of Essential Medicines.[5][6] In the United Kingdom a month of treatment cost the National Health Service 450 to 750 pounds.[4]

Medical uses

When used to treat Hodgkin's lymphoma, it is often delivered as part of the BEACOPP regimen that includes bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (tradename Oncovin), prednisone, and procarbazine. The first combination chemotherapy developed for Hodgkin's lymphoma (HL), MOPP also included procarbazine (ABVD has supplanted MOPP as standard first line treatment for HL, with BEACOPP as an alternative for advanced/unfavorable HL). Alternatively, when used to treat certain brain tumors (malignant gliomas), it is often dosed as PCV when combined with lomustine (often called CCNU) and vincristine.

Dose should be adjusted for kidney disease or liver disease.

Side effects

Very common (greater than 10% of people experience them) adverse effects include loss of appetite, nausea and vomiting.[2] Other side effects of unknown frequency include reduction in leukocytes, reduction in platelets, reduction in neutrophils, which can lead to increased infections including lung infections; severe allergy-like reactions that can lead to angioedema and skin reactions; lethargy; liver complications including jaundice and abnormal liver function tests; reproductive effects including reduction in sperm count and ovarian failure.[2]

When combined with ethanol, procarbazine may cause a disulfiram-like reaction in some people.[2]

It weakly inhibits MAO in the gastrointestinal system, so it can cause hypertensive crises if associated with the ingestion of tyramine-rich foods such as aged cheeses; this appears to be rare.[2]

Procarbazine rarely causes chemotherapy-induced peripheral neuropathy,[7] a progressive, enduring, often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs.[8]

Pharmacology

Procarbazine works, in part, as an alkylating agent and methylates guanine at the O-6 position (much like dacarbazine also does[9]). Guanine is one of the four nucleotides that makes up DNA. The methylated DNA is prone to breakage, and RNA and protein synthesis is inhibited.[10] Proliferating cancer cells need to replicate their DNA and undergo programmed cell death (apoptosis) in response to DNA strand breaks. Normal or non-proliferating cells are more apt to repair the DNA damage, but still some of the healthy cells will be damaged. Procarbazine is metabolized in the liver to an azo-derivative and then further metabolized by the cytochrome P-450 system to an active azoxy-derivative.

References
  1. "Procarbazine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. "Procarbazine Capsules 50mg – Summary of Product Characteristics". UK Electronic Medicines Compendium. 24 November 2014. Archived from the original on 20 December 2016.
  3. World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 228. hdl:10665/44053. ISBN 9789241547659.
  4. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 606. ISBN 9780857111562.
  5. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  7. DeAngelis LM, Posner JS (2003). "Nonmetastatic Complications". In Kufe DW, Pollock RE, Weichselbaum RR, et al. (eds.). Holland-Frei Cancer Medicine (6th ed.). Hamilton (ON): BC Decker. Archived from the original on 2017-09-11.
  8. del Pino BM (Feb 23, 2010). "Chemotherapy-induced Peripheral Neuropathy". NCI Cancer Bulletin. 7 (4): 6. Archived from the original on 2011-12-11.
  9. Mauz-Körholz C, Hasenclever D, Dörffel W, Ruschke K, Pelz T, Voigt A, et al. (August 2010). "Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study". Journal of Clinical Oncology. 28 (23): 3680–3686. doi:10.1200/JCO.2009.26.9381. PMID 20625128.
  10. Newton H (2006). Handbook of Brain Tumor Chemotherapy. Academic Press. ISBN 978-0-12-088410-0. Retrieved 1 January 2021.
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