Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Nitrosoureas:

      • "Nitrosourea" represents a class of compounds (and the name of the molecule) that includes both a nitroso group (R-NO) and a urea group.

        • Nitroso represents a functional group having the NO group attached to an organic moiety (R).	Urea: a.k.a. carbamide. This chemical, CO(NH2)2, consists of two -NH2 groups joined by a carbonyl (C=O) functional group.

    • Nitrosoureas have significant use clinically in management of brain tumors (e.g. glioblastoma multiforme) and may also be used in treating lymphomas.

      • Some nitrosoureas have a role also at high doses in the context of bone marrow transplants.¹

    • Carmustine (BiCNU, Gliadel wafer) and Lomustine

      •  

        "Targeted Treatments in Brain Surgery, Radiation, and Chemotherapy"

        Attribution: Boockvar JA Targeted Treatments in Brain Surgery, Radiation, and Chemotherapy https://www.youtube.com/watch?v=JMIHQFI-RMU American Brain Tumor Association Youtube Channel:  https://www.youtube.com/channel/UCsK91mnT112KibIFx8anlHQ Carmustine wafer use at time 23.28 in video

      •  

        Carmustine (BiCNU, Gliadel Wafer)

      •  

        Lomustine

      • Carmustine is classified as a cell-cycle nonspecific alkylating anticancer drug and is a member of the anti-neoplastic class of drugs described as nitrosoureas.⁶

        • Carmustine cross-links DNA and alkylates during all cell cycle phases.

          • The consequence of these actions interferes with DNA function resulting in cell cycle arrest and programmed cell death (apoptosis).

            • Enhancement of the cytotoxic activity is associated with protein carbamoylation which interferes with DNA repair enzyme activity.

        • The highly lipophilic character of carmustine and lomustine allows these drugs to cross the blood brain barrier.⁶

          • The ability of these drugs to cross the blood brain barrier, because of their highly lipophilic nature, is important given the prominence of these agents in brain tumor treatment.¹

      • The principal mechanism of action of carmustine is DNA alkylation at the the O⁶-guanine position.

        • The adduct formed at the site is a substrate for the repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT).

        • However, methylation of the MGMT promoter inhibits expression of the DNA repair enzyme in about a third of primary gliomas.

        • This inhibition of the repair enzyme promotes sensitivity to nitrosourea anticancer agents.

    • Absorption, Distribution, Metabolism, Excretion:

      • Nitrosoureas are unstable in aqueous environments.²

      • Following IV administration, the half-life in plasma varies from 15 min. to an excess of 90 min.¹

      • From 30%-80% of drug appears in the urine as degradation products within a day and about 60%-70% found in the urine within four days. About 10% is associated with respiratory CO₂.^1,6 

      • Alkylating metabolites gain entry into the CSF and CSF concentrations approximate 15%-30% of the associated plasma values.¹

    • Some Clinical Uses:

      • Carmustine and lomustine have been promoted for use in brain tumors and Hodgkin's disease.⁶ 

        • Carmustine appears useful also in treating non-Hodgkin's lymphoma and multiple myeloma.

          • The agent may be administered intravenously or incorporated into a wafer implanted directly into the CNS (brain) following tumor resection (Gliadel Wafer).

            • The implantable carmustine wafer may be employed as an adjunct to surgery in cases of recurrent glioblastoma multiforme.¹

              •  

                Carmustine as Gliadel Wafer

                Attribution: Rainov NG Heidecke V Clinical Development of Experiment Therapies for Malignant Glionam SQU Med J Feb 2011, Vol. 11, Iss 1  pp 5-28. "A: A single wafer is removed from the sterile aluminium foil protective packaging. B: All 8 Gliadel® wafers belonging to a complete pack are removed from the packaging and prepared for intracerebral implantation. C: Gliadel® wafers lining the wall of a glioblastoma (GBM) resection cavity. Note that the relatively small tumour resection cavity can only accommodate 5 wafers. Slight overlapping of wafers is acceptable. D: Implanted wafers are covered with oxidised cellulose (Surgicel®, Ethicon, Hamburg, Germany) to prevent dislocation and intracavitary movement." https://www.researchgate.net/publication/51066614_Clinical_Development_of_Experimental_Therapies_for_Malignant_Glioma

        • Carmustine high lipophilicity precludes a totally aqueous IV formulation; therefore, the agent is administered in 10% ethanol.

        • Carmustine degrades rapidly following IV administration; however, lomustine is more stable allowing oral use and is available in capsule form.⁶

    • Adverse Effects:

      • Generally, the nitrosourea group including carmustine and lomustine induce significant and delayed myelosuppression.¹ 

        • Myelosuppression can manifest as both thrombocytopenia and leukopenia and may result in significant infection in hemorrhage.² 

        • Recovery, following a single dose may require an excess of a month.

        • Long-term administration of nitrosoureas, particularly semustine, a methylated carmustine derivative, may result in renal failure.

        • Nitrosoureas generally are both mutagenic and highly carcinogenic.¹

        • Both acute and delayed pulmonary toxicity also presents risk.

          • Pulmonary toxicity appears dose-related and administration of these agents in childhood (or early adolescence) appears associated with higher risk for delayed adverse pulmonary effects.²