BCNU

Carmustine is a bicyclohexylnitrosourea (BCNU, Fig. 3) with broad spectrum of antineoplastic activity (e.g., lymphomas, multiple myeloma, sarcomas, brain tumors, gastrointestinal tumors, melanomas). At doses of 80-200 mg/m2 it is given i.v. at 6 week s intervals. 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

BCNU has been incorporated into PCPP-SA 20 80 in two different ways (10). These involve either (1) triturating the dry powdered BCNU with similarly treated polymer and pressing weighed aliquots of the mixture in a Carver press, or (2) codissolving polymer and BCNU in methylene chloride, evaporating the solvent, and pressing the resulting material as in method 1. The former method produces a soUd mixture of BCNU and polymer, while the latter method... 

These two methods produce different release profiles in vitro. Figure 5 demonstrates the release kinetics of BCNU from wafers loaded with 2.5% BCNU pressed from materials produced using these two methods. The wafers containing tritiated BCNU were placed into beakers containing 200-ml aliquots of 0.1 M phosphate buffer, pH 7.4, which were placed in a shaking water bath maintained at 37 C. The shaking rate was 20 cycles/min to avoid mechanical disruption of the wafers. The supernatant fluid was sampled periodically, and the BCNU released was determined by liquid scintillation spectrometry. The BCNU was completely released from the wafers prepared by the trituration method within the first 72 hr, whereas it took just about twice as long for the BCNU to be released from wafers... 

FIGURE 5 Release of [ HJBCNU from compression-molded discs of PCPP-SA, 20 80. Disks 3 mm in diameter and 1 mm thick containing 2.5% [3h]BCNU were prepared by compression molding using either the trituration or solution methods described in the text. In vitro release of ( H]BCNU was measured as described in the text. 

The difference in rates of release of BCNU from wafers produced by the trituration or solution methods is also seen in vivo (11,14), as is shown in Fig. 6. Wafers of PCPP-SA 20 80 were prepared by either the solution or trituration methods, as described above, and were implanted into the brains of rabbits. The animals were sacrificed at various times after implantation and the brains were removed, fixed, and processed for quantitative autoradiography. To quantitate the percentage of the brain exposed to BCNU released from these wafers, the following calculation was performed. The percentage of the brain in which the radioactivity from the tritiated BCNU released from the wafers exceeded the background counts by at least two standard deviation units was plotted as a function of time following implantation in Fig. 6. A control set of rabbits had a solution of BCNU injected directly into the same location in the... 

Figure 6 also shows that the use of this polymeric delivery system, also known as the BIODEL polymeric drug delivery system, for BCNU greatly increases the time over which the brains of these animals are exposed to significant BCNU concentrations. The brains... 

Since these studies utilized autoradiographic techniques, it was important to determine the chemical nature of the material measured using radiochemical procedures. Using punch biopsies of the brain slices which were measured autoradiographically, it was shown using thin-layer chromatography that about 30% of the radioactivity was associated with unchanged BCNU (14). It was therefore concluded that the measurements described above accurately reflect brain concentrations of BCNU. 

FIGURE 7 Movement of ( HJBCNU-associated radioactivity through rabbit brain. Radioactivity resulting from [ H]BCNU was measured at various distances from the implantation site following implantation of discs described for Fig. 5 into the brains of rabbits. Details of the experimental procedure are described in the text. 

R., Chasin, M., Tamargo, R., and Colvin, O, M., The intracerebral delivery of BCNU with surgically implanted biodegradable polymers A quantitative autoradiographic study, Proc. 

Brem, H., Tamargo, R. J., Finn, M., and Chasin, M., Biocompatibility of a BCNU-loaded biodegradable polymer A toxicity study in primates, Abstracts of the 1988 Annual Meeting of the American Association of Neurological Surgeons, 1988,... 

The GSH reductase inhibitor l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) also promotes corneal swelling in the isolated cornea. The addition of GSH prevents the action of BCNU as the cornea needs a constant supply of NADPH for maintaining adequate concentrations of reduced glutathione for the detoxification of hydrogen peroxide. It has been shown that hydrogen peroxide and BCNU primarily affect the permeability of the endothelial cells rather than the active processes transporting sodium and chloride ions across the membrane (Riley, 1985). 

BCF Basophil chemotactic factor B-CFC Basophil colony-forming cell BCG Bacillus Calmette-Guerin BCNU l,3-bis(2-chloroethyl)-l-nitrosourea bFGF Basic fibroblast growth fiictor Bg Birbeck granules BHR Bronchial hyperresponsiveness BHT Butylated hydroxyroluene b.i.d. Bis in die (twice a day)... 

Starch (Spherex) 40 Intra-arterial administration of cytostatics 5-Fluorouracil, hepatic BCNU, renal actinomycin D... 

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH provided from the hexose monophosphate pathway. GR, a ubiquitous flavoenzyme, maintains a high value of two for the GSH/GSSG ratio in the red blood cells. l,3-Bis(2-chloroethyl)-nitrosourea (BCNU) selectively inhibits cellular GR. GR is composed of two identical subunits, each of molecular mass 50 kDa (S8). The three-dimensional structure and mechanism of catalysis have been established for human GR (K17). 

BCNU is synthesized by treating phosgene with ethyleneimine without the addition of a base to take up the HCl liberated. Reaction of the intermediate urea (46) in situ with hydrogen chloride serves to open the aziridine rings to afford sym-bis-2-chlorethylurea (47). This is nitrosated with sodium nitrite in formic acid to give BCNU (48). 

Dexa-BEAM dexamethasone/ carmustine (BCNU)/ etoposide (VP-16)/ cytarabine (Ara-C)/ melphalan Dexamethasone 8 mg PO Q8H days 1 -10 BCNU 60 mg/M2 IV day 2 VP-16 75 mg/M2 IV days 4-7 Ara-C 100 mg/M2 IVQ12H days 4-7 Melphalan 20 mg/M2 IV day 3 REF Pfreundschuh etal. J Clin Oncol 1994 12 580-586 PREMEDICATIONS 1. Kytril 1 mg PO/IV 30 minutes before and 12 hours after chemotherapy on days 2 and 3 2. Compazine 10 mg PO/IV 30 minutes before chemotherapy on days 4-7 OTHER MEDICATIONS 1. Give non-cisplatin delayed emesis prophylaxis Repeat every 28 days Carmustine—maximum total dose is 1440 mg/M2 causes delayed myelosuppression... 

Regimen- dacarbazine BCNU 150 mg/M2 IV day 1 of every other cycle... 

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