MedKoo product information:

 Procarbazine Hydrochloride

procarbazine hydrochloride is the hydrochloride salt of a methylhydrazine derivative with antineoplastic and mutagenic activities. Although the exact mode of cytotoxicity has not been elucidated, procarbazine, after metabolic activation, appears to inhibit the trans-methylation of methionine into transfer RNA (t-RNA), thereby preventing protein synthesis and consequently DNA and RNA synthesis. This agent may also undergo auto-oxidation, resulting in the formation of cytotoxic free radicals which damage DNA through an alkylation reaction. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

DRUG DESCRIPTION

Matulane (procarbazine hydrochloride), a hydrazine derivative antineoplastic agent, is available as capsules containing the equivalent of 50 mg procarbazine as the hydrochloride. Each capsule also contains cornstarch, mannitol and talc. Gelatin capsule shells contain parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10. Chemically, procarbazine hydrochloride is N-isopropyl-α-(2-methylhydrazino)-p-toluamide monohydrochloride. It is a white to pale yellow crystalline powder which is soluble but unstable in water or aqueous solutions. The molecular weight of procarbazine hydrochloride is 257.76

CLINICAL PHARMACOLOGY

The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA. Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine. Procarbazine is rapidly and completely absorbed. Following oral administration of 30 mg of 14C-labeled procarbazine, maximum peak plasma radioactive concentrations were reached within 60 minutes. After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes. Approximately 70% of the radioactivity is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of 14C-labeled procarbazine. Procarbazine crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.

  1: Yap KY, Tay WL, Chui WK, Chan A. Clinically relevant drug interactions between anticancer drugs and psychotropic agents. Eur J Cancer Care (Engl). 2009 Dec 17. [Epub ahead of print] PubMed PMID: 20030690.

2: Roos WP, Nikolova T, Quiros S, Naumann SC, Kiedron O, Zdzienicka MZ, Kaina B. Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O(6)-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs. DNA Repair (Amst). 2009 Jan 1;8(1):72-86. Epub 2008 Oct 21. PubMed PMID: 18840549.

3: Ribrag V, Koscielny S, Casasnovas O, Cazeneuve C, Brice P, Morschhauser F, Gabarre J, Stamatoullas A, Lenoir G, Salles G; Groupe d'Etude des Lymphomes agressifs group, Laboratoire de Génétique et de recherche translationnelle, and Institut Gustave Roussy. Pharmacogenetic study in Hodgkin lymphomas reveals the impact of UGT1A1 polymorphisms on patient prognosis. Blood. 2009 Apr 2;113(14):3307-13. Epub 2008 Sep 3. PubMed PMID: 18768784.

4: Krawczuk-Rybak M, Leszczyńska E, Wysocka J, Zelazowska-Rutkowska B. [Anti-mullerian hormone in young women after chemotherapy and infradiaphragmatic radiotherapy for childhood cancer]. Pediatr Endocrinol Diabetes Metab. 2008;14(2):99-103. Polish. PubMed PMID: 18721496.

5: Glen CD, Smith AG, Dubrova YE. Single-molecule PCR analysis of germ line mutation induction by anticancer drugs in mice. Cancer Res. 2008 May 15;68(10):3630-6. PubMed PMID: 18483245.

6: Gasowska-Bajger B, Wojtasek H. Indirect oxidation of the antitumor agent procarbazine by tyrosinase--possible application in designing anti-melanoma prodrugs. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3296-300. Epub 2008 Apr 22. PubMed PMID: 18457951.

7: Armand JP, Ribrag V, Harrousseau JL, Abrey L. Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors. Ther Clin Risk Manag. 2007 Jun;3(2):213-24. PubMed PMID: 18360630; PubMed Central PMCID: PMC1936303.

8: Grossman SA, Carson KA, Batchelor TT, Lesser G, Mikkelsen T, Alavi JB, Phuphanich S, Hammour T, Fisher JD, Supko JG. The effect of enzyme-inducing antiseizure drugs on the pharmacokinetics and tolerability of procarbazine hydrochloride. Clin Cancer Res. 2006 Sep 1;12(17):5174-81. PubMed PMID: 16951236.

9: Giordana MT, Ghimenti C, Leonardo E, Balteri I, Iudicello M, Duò D. Molecular genetic study of a metastatic oligodendroglioma. J Neurooncol. 2004 Feb;66(3):265-71. PubMed PMID: 15015656.

10: Ewesuedo RB, Dolan ME. Pharmacokinetics of oral O6-benzylguanine and evidence of interaction with oral ketoconazole in the rat. Cancer Chemother Pharmacol. 2000;46(2):150-5. PubMed PMID: 10972485.

11: Durmaz R, Deliorman S, Uyar R, Işiksoy S, Erol K, Tel E. The effects of anticancer drugs in combination with nimodipine and verapamil on cultured cells of glioblastoma multiforme. Clin Neurol Neurosurg. 1999 Dec;101(4):238-44. PubMed PMID: 10622452.

12: Lishner M, Manor Y, Kitay-Cohen Y, Avishay AE. Association between alopecia and response to aggressive chemotherapy in patients with Hodgkin's disease. Med Hypotheses. 1999 Nov;53(5):447-9. PubMed PMID: 10616048.

13: Meurman JH, Laine P, Keinànen S, Pyrhönen S, Teerenhovi L, Lindqvist C. Five-year follow-up of saliva in patients treated for lymphomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Apr;83(4):447-52. PubMed PMID: 9127375.

14: Witt KL, Bishop JB. Mutagenicity of anticancer drugs in mammalian germ cells. Mutat Res. 1996 Aug 17;355(1-2):209-34. Review. PubMed PMID: 8781584.

15: Haselsberger K, Peterson DC, Thomas DG, Darling JL. Assay of anticancer drugs in tissue culture: comparison of a tetrazolium-based assay and a protein binding dye assay in short-term cultures derived from human malignant glioma. Anticancer Drugs. 1996 May;7(3):331-8. PubMed PMID: 8792008.

16: Holt A, Callingham BA. Further studies on the ex-vivo effects of procarbazine and monomethylhydrazine on rat semicarbazide-sensitive amine oxidase and monoamine oxidase activities. J Pharm Pharmacol. 1995 Oct;47(10):837-45. PubMed PMID: 8583353.

17: Niitsu N, Umeda M. COP-BLAM regimen combined with granulocyte colony-stimulating factor and high-grade non-Hodgkin's lymphoma. Eur J Haematol. 1995 Aug;55(2):88-92. PubMed PMID: 7543059.

18: Kangasniemi M, Wilson G, Parchuri N, Huhtaniemi I, Meistrich ML. Rapid protection of rat spermatogenic stem cells against procarbazine by treatment with a gonadotropin-releasing hormone antagonist (Nal-Glu) and an antiandrogen (flutamide). Endocrinology. 1995 Jul;136(7):2881-8. PubMed PMID: 7789313.

19: Ember I, Raposa T, Varga C, Herceg L, Kiss I. Carcinogenic effects of cytostatic protocols in CBA/Ca mice. In Vivo. 1995 Jan-Feb;9(1):65-9. PubMed PMID: 7545447.

20: Look MP, Musch E. Lipid peroxides in the polychemotherapy of cancer patients. Chemotherapy. 1994 Jan-Feb;40(1):8-15. PubMed PMID: 8306820.

21: Boucher R, Livingston GK, Que Hee SS. In vitro micronucleus bioassay of human peripheral lymphocytes for adriamycin in the presence of cyclophosphamide and urines of patients administered anticancer drugs. Environ Mol Mutagen. 1993;21(4):372-82. PubMed PMID: 8491217.

22: Laine P, Meurman JH, Tenovuo J, Murtomaa H, Lindqvist C, Pyrhönen S, Teerenhovi L. Salivary flow and composition in lymphoma patients before, during and after treatment with cytostatic drugs. Eur J Cancer B Oral Oncol. 1992 Oct;28B(2):125-8. PubMed PMID: 1284874.

23: Holt A, Sharman DF, Callingham BA. Effects in-vitro of procarbazine metabolites on some amine oxidase activities in the rat. J Pharm Pharmacol. 1992 Jun;44(6):494-9. PubMed PMID: 1359074.

24: Goria-Gatti L, Iannone A, Tomasi A, Poli G, Albano E. In vitro and in vivo evidence for the formation of methyl radical from procarbazine: a spin-trapping study. Carcinogenesis. 1992 May;13(5):799-805. PubMed PMID: 1316811.

25: Paolucci G, Rosito P, Di Caro A. [Late data in pediatric oncology]. Pediatr Med Chir. 1990 Jul-Aug;12(4):323-7. Review. Italian. PubMed PMID: 2075095.

26: Newman MA, Hee SQ, Schoeny R, Lowry L. Biological monitoring screening of patients provided antineoplastic drugs including adriamycin, cyclophosphamide, 5-fluorouracil, methotrexate, and vincristine. Cancer Res. 1990 Jun 1;50(11):3351-66. PubMed PMID: 2334930.

27: Teicher BA, Holden SA, al-Achi A, Herman TS. Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res. 1990 Jun 1;50(11):3339-44. PubMed PMID: 2334928.

28: Millward MJ, Cohney SJ, Byrne MJ, Ryan GF. Pulmonary toxicity following MOPP chemotherapy. Aust N Z J Med. 1990 Jun;20(3):245-8. Review. PubMed PMID: 2196871.

29: Velez de la Calle JF, Jégou B. Protection by steroid contraceptives against procarbazine-induced sterility and genotoxicity in male rats. Cancer Res. 1990 Feb 15;50(4):1308-15. PubMed PMID: 2137028.

30: Abdyldaev RA, Dyĭkanbaeva SK. [The efficacy of combined chemotherapy in lymphogranulomatosis]. Ter Arkh. 1990;62(7):132-5. Russian. PubMed PMID: 2251652.

31: Swaffar DS, Horstman MG, Jaw JY, Thrall BD, Meadows GG, Harker WG, Yost GS. Methylazoxyprocarbazine, the active metabolite responsible for the anticancer activity of procarbazine against L1210 leukemia. Cancer Res. 1989 May 1;49(9):2442-7. PubMed PMID: 2706632.

32: Basch PF, Clemens LE. Schistosoma mansoni: reversible destruction of testes by procarbazine. Comp Biochem Physiol C. 1989;93(2):397-401. PubMed PMID: 2572394.

33: Slavik M, Narasimhan TR, Riley C, Slavik J. Changes in serum copper and zinc during treatment with anticancer drugs interfering with pyridoxal phosphate. Adv Exp Med Biol. 1989;258:235-42. PubMed PMID: 2516708.

34: Geyer JR, Pendergrass TW, Milstein JM, Bleyer WA. Eight drugs in one day chemotherapy in children with brain tumors: a critical toxicity appraisal. J Clin Oncol. 1988 Jun;6(6):996-1000. PubMed PMID: 3373269.

35: Kinoshita S, Bandou H, Yamashita T, Fukuta K, Yamasaki K, Matsuura A, Shimizu E, Ogura T, Doi H, Nakamura T, et al. [Randomized comparative study of CE (CDDP plus etoposide) and CE-AVN (ACNU, VCR plus procarbazine) as combined anticancer chemotherapy in small cell cancer of the lung]. Gan To Kagaku Ryoho. 1988 Apr;15(4 Pt 1):643-8. Japanese. PubMed PMID: 2833178.

36: Horstman MG, Meadows GG, Yost GS. Separate mechanisms for procarbazine spermatotoxicity and anticancer activity. Cancer Res. 1987 Mar 15;47(6):1547-50. PubMed PMID: 3815355.

37: Newell D, Gescher A, Harland S, Ross D, Rutty C. N-methyl antitumour agents. A distinct class of anticancer drugs? Cancer Chemother Pharmacol. 1987;19(2):91-102. Review. PubMed PMID: 3552281.

38: Prokopowicz J, Kemona H, Wysocka J, Kiluk S. Serum lysozyme activity in patients with Hodgkin's disease undergoing chemotherapy. Folia Haematol Int Mag Klin Morphol Blutforsch. 1987;114(3):338-47. PubMed PMID: 2444507.

39: Floersheim GL, Bieri A, Chiodetti N. Xenografts in pharmacologically immunosuppressed mice as a model to test the chemotherapeutic sensitivity of human tumors. Int J Cancer. 1986 Jan 15;37(1):109-14. PubMed PMID: 3455687.

40: Alley MC, Powis G, Appel PL, Kooistra KL, Lieber MM. Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines. Cancer Res. 1984 Feb;44(2):549-56. PubMed PMID: 6692360.

41: Vacca M, Preziosi P. Tolerance to pituitary-adrenal axis activation by anticancer drugs in normal and tumour-bearing rats. Arch Toxicol Suppl. 1984;7:98-102. PubMed PMID: 6596030.

42: Ettlin RA, Bechter R, Lee IP, Hodel C. Aspects of testicular toxicity induced by anticancer drugs. Arch Toxicol Suppl. 1984;7:151-4. PubMed PMID: 6595975.

43: Hodel C, Ettlin RA, Zschauer A. Morphological changes produced in rat testis by anticancer drugs. Arch Toxicol Suppl. 1984;7:147-50. PubMed PMID: 6595974.

44: Bonadonna G, Santoro A, Viviani S, Lombardi C, Ragni G. Gonadal damage in Hodgkin's disease from cancer chemotherapeutic regimens. Arch Toxicol Suppl. 1984;7:140-5. PubMed PMID: 6083763.

45: Soloway AH, Brumbaugh RJ, Witiak DT. Carbinolamines and related structures--potential alkylating metabolites of clinically active anticancer drugs. J Theor Biol. 1983 Jun 7;102(3):361-73. PubMed PMID: 6225911.

46: Morgan D, Freshney RI, Darling JL, Thomas DG, Celik F. Assay of anticancer drugs in tissue culture: cell cultures of biopsies from human astrocytoma. Br J Cancer. 1983 Feb;47(2):205-14. PubMed PMID: 6297528; PubMed Central PMCID: PMC2011276.

47: Chryssanthou CP, Wallach RC, Atchison M. Meiotic chromosomal changes and sterility produced by nitrogen mustard and procarbazine in mice. Fertil Steril. 1983 Jan;39(1):97-102. PubMed PMID: 6848396.

48: Shiba DA, Weinkam RJ. The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF1 mice and the effects of pretreatment with procarbazine, phenobarbital, diphenylhydantoin, and methylprednisolone upon in vivo procarbazine activity. Cancer Chemother Pharmacol. 1983;11(2):124-9. PubMed PMID: 6627598.

49: Floersheim GL. Comparative growth of human tumors in pharmacologically immunosuppressed, immune-deprived, cyclosporin A-treated and nude mice. Eur J Cancer Clin Oncol. 1982 Jun;18(6):589-94. PubMed PMID: 6749512.

50: Shiba DA, Weinkam RJ. Quantitative analysis of procarbazine, procarbazine metabolites and chemical degradation products with application to pharmacokinetic studies. J Chromatogr. 1982 May 14;229(2):397-407. PubMed PMID: 7096474.

51: Bechter R, Ettlin RA, Dixon RL. Assessment of testicular toxicity associated with anticancer agents II. Sperm counts and serial mating. Proc West Pharmacol Soc. 1982;25:385-7. PubMed PMID: 7122525.

52: Gola A, Orzechowska-Juzwenko K. Toxicity interactions and ways of reducing side effects of anticancer drugs. Folia Haematol Int Mag Klin Morphol Blutforsch. 1982;109(4):521-32. PubMed PMID: 6184274.

53: Ettlin RA, Bechter R, Dixon RL. Assessment of testicular toxicity associated with anticancer agents I. Histopathology. Proc West Pharmacol Soc. 1982;25:381-4. PubMed PMID: 6181518.

54: Floersheim GL, Nassenstein D, Torhorst J. Growth of human tumors in mice after short-term immunosuppression with procarbazine, cyclophosphamide, and antilymphocyte serum. Transplantation. 1980 Oct;30(4):275-80. PubMed PMID: 6934635.

55: Dienstbier Z, Blehová Z, Masopust J, Sámal M. Individual changes of DNA catabolite excretion in the course of antitumor therapy of Hodgkin's disease. Strahlentherapie. 1980 Apr;156(4):240-3. PubMed PMID: 7368228.

56: Soots A, Häyry P. Prolongation of rat cardiac allograft survival by donor pretreatment. Screening of antineoplastic drugs. Transplantation. 1978 May;25(5):259-64. PubMed PMID: 349802.

57: Chabner BA, Myers CE, Oliverio VT. Clinical pharmacology of anticancer drugs. Semin Oncol. 1977 Jun;4(2):165-91. PubMed PMID: 69319.

58: Horton J, Mittelman A, Taylor SG 3rd, Jurkowitz L, Bennett JM, Ezdinli E, Colsky J, Hanley JA. Phase II trials with procarbazine (NSC-77213), streptozotocin (NSC-85998), 6-THIOGUANINE (NSC-752), and CCNU (NSC-79037) in patients with metastatic cancer of the large bowel. Cancer Chemother Rep. 1975 Mar-Apr;59(2 Pt 1):333-40. PubMed PMID: 125147.

59: Montgomery JA, Struck RF. The relationship of the metabolism of anticancer agents to their activity. Prog Drug Res. 1973;17:320-409. Review. PubMed PMID: 4150245.