Degradation and inactivation of antitumor drugs.

Chemical methods for the degradation of 11 antineoplastic drugs [etoposide, teniposide, bleomycin, mitomycin C, cisplatin, cis-dichloro-trans-dihydroxy-bis(isopropylamine) platinum IV (CHIP), cyclophosphamide, ifosfamide, carmustine, lomustine, and methotrexate] were investigated. The success of the degradation procedures was assessed by HPLC and degree of biological inactivation by mutagenicity assays. The most widely applicable procedure was oxidation with potassium permanganate or 5.25% sodium hypochlorite solution (bleach). Oxidation completely degraded and inactivated etoposide, teniposide, bleomycin, mitomycin C, and methotrexate. In addition, oxidation followed by nucleophilic substitution resulted in the complete degradation and inactivation of cyclophosphamide and ifosfamide. Although carmustine and lomustine were chemically degraded by treatment with acidic potassium permanganate, the resulting reaction mixtures remained mutagenic. Therefore, this procedure cannot be recommended. The platinum-containing compounds, cisplatin and CHIP, were rendered nonmutagenic by reaction with sodium diethyldithiocarbamate. These easily performed, relatively safe procedures can be used to prevent exposure to mutagenic wastes and spills in the hospital setting.

Inhibition of T-lymphocyte proliferation by the cyclic polypeptide didemnin B: no inhibition of lymphokine stimulation.

We investigated possible mechanisms by which the cyclic depsipeptide didemnin B (DB) inhibits lymphocyte proliferation. DB inhibited the proliferation of Con-A stimulated murine splenocytes, the interleukin-2 (IL-2) dependent proliferation of the CTLL-2 cell line, and the interleukin 4 (IL 4) dependent growth of both CTLL-2 and D10.G.4.1 cell lines at approximately equimolar concentrations (SD50 = 3 to 10 X 10(-9)M). Inhibition of CTLL-2 growth by 10(-8)M DB was partially reversible, and significantly blocked the incorporation of [3H]-thymidine even when added 24 hr after initial IL 2 stimulation. Concentrations of DB (10(-8)M) that completely blocked mitogen-driven spleen cell blastogenesis only partially inhibited the synthesis and secretion of IL-2. Although DB blocked the growth of T lymphocyte clones in response to both recombinant human IL 2 and recombinant murine IL 4, the suppression was not due to an uncoupling of lymphokinetic signaling but was closely correlated with an inhibition of protein and RNA synthesis. Addition of DB to an in vitro translation system did not inhibit protein synthesis. Thus, we conclude that DB functions as an antiproliferative, and not as a specifically immunosuppressive, compound.

Permeability of four disposable protective-clothing materials to seven antineoplastic drugs.

The permeability of four types of protective-clothing material to seven injectable antineoplastic drugs was studied. The protective materials tested were Saranex-laminated Tyvek, polyethylene-coated Tyvek, nonporous Tyvek, and Kaycel. Circles 6 cm in diameter were cut from a single garment of each material and exposed to each drug. Permeation of cisplatin, etoposide, mitomycin, cyclophosphamide, carmustine, and thiotepa was assessed by the Salmonella mutagenicity test after four hours of exposure. Doxorubicin permeation was assessed qualitatively over an eight-hour exposure period using a coloration assay. Saranex-laminated Tyvek was not permeable under the test conditions. Polyethylene-coated Tyvek was slightly permeable to thiotepa and carmustine. Nonporous Tyvek was permeable to all seven drugs, and the Kaycel garment was permeable to all of the drugs except etoposide. In no instance did permeation exceed 3.3% of the applied drug dose. Saranex-laminated Tyvek was the most protective of the barrier garments, followed closely in effectiveness by the polyethylene-coated Tyvek. Clothing made from these two Tyvek composites would allow less air flow and, therefore, would be less comfortable to wear for extended periods. Garments made of nonporous Tyvek or Kaycel would be more comfortable, but their use should be accompanied by an awareness of their potential permeability to certain antineoplastic drugs.

Permeability of latex and polyvinyl chloride gloves to 20 antineoplastic drugs.

Permeability of latex and polyvinyl chloride (PVC) gloves to 20 injectable antineoplastic drugs was studied. Four types of gloves were evaluated: latex surgical gloves, latex examination gloves, and PVC gloves in two thicknesses. Each glove material was exposed to each drug for 90 minutes, and permeation was tested using a mutagenicity assay. Individual fingertips of thin PVC gloves and latex surgical gloves were tested for permeability at five time points (2-30 minutes) using a doxorubicin coloration assay. All drugs permeated the thin PVC gloves. Latex surgical gloves were definitely permeable to two drugs (carmustine and thiotepa) and exhibited borderline permeability to mechlorethamine hydrochloride. The thick PVC gloves were definitely permeable to four drugs (carmustine, thiotepa, mechlorethamine hydrochloride, and daunorubicin hydrochloride) and exhibited borderline permeability to two drugs (doxorubicin and mercaptopurine). The latex examination gloves were permeable to carmustine, thiotepa, mechlorethamine hydrochloride, and cyclophosphamide. Doxorubicin permeation of individual fingertips of thin PVC gloves varied in time and amount. Doxorubicin did not permeate the latex surgical glove material, but testing with thiotepa showed that individual fingertips of this material also varied in permeability. Glove thickness was a major determinant of permeability; latex surgical gloves were the least permeable and thin PVC gloves the most permeable to the antineoplastic drugs tested. Within individual gloves and glove types, time and amount of permeation were not uniform.

Permeability of latex and polyvinyl chloride gloves to carmustine.

Permeability of latex and polyvinyl chloride gloves to the antineoplastic agent carmustine was studied. The latex gloves were of two types: sterile surgical gloves and disposable utility gloves. Polyvinyl chloride gloves of two thicknesses (0.20 mm and 0.35 mm) were tested. Both single and double thicknesses of each material were exposed to carmustine 3.33 mg/ml in a 10% aqueous solution of ethanol, and to the solvent alone, for 5-90 minutes. Permeation of carmustine was tested using a mutagenicity assay and a chemical assay. A time-dependent increase in carmustine permeation was observed for all types of materials (both double and single thicknesses). Mean amounts of carmustine permeating single gloves at 90 minutes ranged from 53 to 86 micrograms for the mutagenicity assay and 49 to 78 micrograms for the chemical assay. Double thicknesses of glove material (especially of the thicker polyvinyl chloride) reduced the amount of drug permeation. These latex and polyvinyl chloride glove materials offer only limited protection against contact exposure to carmustine. Latex surgical gloves may be slightly less permeable than the other types tested.