John D. Roberts

A phase i clinical trial of didemnin B

Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug‐induced liver dysfunction. Thirty‐five patients with advanced cancer received didemnin B according to a 5‐day bolus schedule with dose levels ranging from 0.03 to 2.00 mg/m2/d. The dose‐limiting toxicity was nausea and vomiting. Sporadic elevation of the hepatic enzyme level occurred but was not dose limiting. Two patients had anaphylactic symptoms possibly related to the 5% polyoxyethylated castor oil (Cremophor EL, BASF, Ludwigshafen, Germany) vehicle during the drug infusion. Clinical bleeding was not observed and myelosuppression was not significant. No partial or complete tumor responses were seen. The recommended Phase II dose for the 5‐day schedule is 1.6 mg/m2/d. Cancer 68:2550–2554, 1991.

Low‐dose cytosine arabinoside in the myelodysplastic syndromes and acute myelogenous leukemia

Seven patients with a myelodysplastic syndrome or “smoldering” acute myelogenous leukemia were treated with cytosine arabinoside in low dosage. Four patients experienced transient, partial responses characterized by improved peripheral blood counts, cessation of transfusion requirements, and a decreased incidence of infection. Treatment was associated with significant, transient hematologic toxicity. The appropriate clinical role of low‐dose cytosine arabinoside remains uncertain.

Nitric Oxide Modulates Lymphocyte Proliferation But Not Secretion of IL-2

The objective of this study was to determine the effects of nitric oxide (NO) on lymphocyte proliferation and cytokine release. Bronchoalveolar lavage (BAL) cells served as the source of NO and were obtained from rats treated with a single, intratracheal dose of bleomycin (3.6 mg/kg). At the time of sacrifice, the spleens were removed and the lymphocytes separated. Co-cultures containing BAL cells, lymphocytes and concanavalin-A were established and incubated at 37 degrees C for 24 hours at which time proliferation, nitrite concentration and interleukin-2 (IL-2) production were measured. At ratios from 5:1 to 1:4 (BAL:lymphocyte) there was a significant reduction in lymphocyte proliferation. There was a significant, negative correlation between NO concentration and thymidine incorporation which was reversed when the NO synthase inhibitor NG-monomethyl-L-arginine (NMA) was added to the co-cultures. Despite marked inhibition of spleen lymphocyte proliferation by NO, released by BAL cells, there was no corresponding reduction in IL-2 production. These data demonstrate that macrophages, activated in vivo, produce NO which regulates lymphocyte growth but not necessarily functions such as the secretion of the cytokine IL-2. Further, the ability of IL-2-dependent CTLL-2 cells to proliferate in the presence of excess IL-2 was also inhibited by BAL cells, confirming that NO inhibits lymphocyte growth.

Water soluble DACHPt(II) complexes: Problems of purification; Stability of complexes with nitrogen-containing ligands

Abstract Two previously reported water soluble 1,2-diaminocyclohexaneplatinum(II) antitumor complexes with nitrogen-containing dicarboxylato ligands (N-substituted iminodiacetato(1,2-diaminocyclohexane)platinum(II) and aminomalonato(1,2-diaminocyclohexane)platinum(II)) were discovered to have significant residual impurities in the chemical formulations. Upon further purification each complex was found to be significantly less active in biological systems than previously reported. Each complex is stable in aqueous solution. This experience suggests that commonly accepted criteria for chemical identification and purity are inadequate for this type of complex. We hypothesize that tridentate bonding between the nitrogen-containing dicarboxylato group and platinum renders these complexes chemically stable and biologically inert.

Metabolism of tiazofurin by human erythrocytes and mononuclear blood cells in vitro

In vitro studies of the uptake, metabolism, and release of tiazofurin by human red blood cells reveal extensive phosphorylation with intracellular trapping of drug predominantly as tiazofurin triphosphate. This phenomenon may explain, in part, the plasma pharmacokinetic profile of tiazofurin. Metabolism of tiazofurin to tiazofurin adenine dinucleotide, the presumed oncolytic metabolite, occurs in mononuclear blood cells but not in erythrocytes.

Regional fibrosis after intraperitoneal administration of mafosfamide

SummaryMafosfamide is a cyclophosphamide analog which, unlike cyclophosphamide, does not require enzymatic activation and does not cause urinary tract toxicity. Administration of mafosfamide intraperitoneally, but not intravenously, causes a delayed, dose-dependent fibrotic peritoneal reaction associated with an increased incidence of delayed mortality. This phenomenon might complicate interpretation of in vivo laboratory studies of activity and toxicity in which the intraperitoneal route of administration is utilized. Further, this toxic effect presents a problem for the clinical development of this agent for regional therapies such as intraperitoneal installation.

Efficacy and toxicity of 4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (ASTA Z 7557, INN mafosfamide) after intraperitoneal administration to mice

Summary4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (AZ; ASTA Z 7557) is a cyclophosphamide (CP) analog designed to be without acute bladder toxicity and to undergo spontaneous activation yielding phosphoramide mustard (PM). Studies in murine systems with intraperitoneal (i.p.) administration suggest that AZ may have a therapeutic index favorable to CP without an associated risk of bladder toxicity. Pericapsular hepatic fibrosis after i.p. administration suggests that regional AZ therapy may cause local toxicity. Further study of this compound, especially with intravenous (i.v.) administration, will be of interest.

Increased systemic, but not regional, neopterin production following intraperitoneal administration of interleukin-2 and lack of effect of pterins upon the lymphokine-activated killer cell phenomenon.

Summary: Circulatin neopterin is derived from monocytes and/or macrophages that produce it upon stinulation by interferon-y released from activated T cells. Neopterin production has been proposed as a marker of biological response in the clinical administration of a number of cytokines. Changes in neopterin production as indicated by urinary neopterin excretion were studied in four patients with ovarian carcinoma receiving intraperitoneal interleukin-2 and lymplhkine-activated killer cells. Neopterin production increased approximately threefold during treatment with interleukin-2 at doses which represent or exceed the maximum tolertated dose by this route of administration. Increased neopterin apparently was derived from systemic, not regional, tissues. The physiologis role(S) of pterins in bimmune responses is ukncertain. In an in vitro system, the presence of neoterin or tetrahydrobiopterin or the pterin synthesis inhibito, N-acetyl serotonin, did ot modulate cytotoxic effects of lymphokine-activated killer cells.