Susan A. King

Hypersensitivity reactions to teniposide (VM-26): an analysis.

An analysis of hypersensitivity reactions to teniposide was approached using three methods: investigator survey, adverse drug reaction analysis, and literature search. By the survey method, hypersensitivity incidence was 6.5% with the majority of the reactions (82%) occurring in brain tumor or neuroblastoma patients. By the second method, 43 cases of hypersensitivity that were reported to the National Cancer Institute (NCI) between January 1983 and October 1985 were analyzed in detail. Reaction onset was unpredictable according to the number of drug doses. The majority of the patients (65%) experiencing the reaction had neuroblastoma or brain tumors, and these patients also tended to react earlier in the course of drug administration than those with hematologic malignancies. Clinical presentation was not correlated with the patients diagnosis. All patients recovered. However, only six of 13 were successfully rechallenged with the drug. The third approach, the literature search, provided information on 82 hypersensitivity reactions among 2,250 patients (3.6% incidence). Forty-five percent of these reactions were linked to neuroblastoma or brain tumor patients. The analysis of hypersensitivity to teniposide by these three methods provides insight into the true incidence of hypersensitivity reactions in the general patient population. The frequency of the reactions is substantially higher in patients with neuroblastoma and brain tumors. This population should be considered for future trials of aggressive prophylactic therapy.

Flavone acetic acid (LM 975, NSC 347512) A novel antitumor agent

SummaryFlavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.

Clinical use of thymidine as a rescue agent from methotrexate toxicity

SummaryThymidine has been available for clinical research as a rescue agent since 1978 under sponsorship of the Division of Cancer Treatment, National Cancer Institute. Renal insufficiency following administration of high dose methotrexate results in prolonged exposure to toxic concentrations of drug. Thymidine has been used in conjunction with leucovorin and alkaline hydration to protect patients with acute renal dysfunction from life-threatening methotrexate toxicity. The outcome of eight cases in which thymidine was released under the special exception mechanism to treat patients who developed acute renal failure following methotrexate are reported. The clinical trials using thymidine in combination with methotrexate in patients with normal renal function are also reviewed.

Arabinosyl-5-azacytosine: A novel nucleoside entering clinical trials

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside. Arabinosyl-5-azacytosine is phosphorylated to the nucleotide level by deoxycytidine kinase. Upon further anabolism to the triphosphate level, it can be incorporated into DNA. The mechanism of cytotoxicity is thought to be related to inhibition of DNA synthesis. Leukemic and solid tumor cell lines that are resistant to cytosine arabinoside due to deletion of deoxycytidine kinase activity are cross-resistant to arabinosyl-5-azacytosine. Unlike cytosine arabinoside, arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinial toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.

Clinical toxicity associated with tiazofurin

SummaryTiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23–36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (≥ grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.

Hypersensitivity reactions to trimetrexate

SummaryTrimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in < 2% of patients.

Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.

Hypersensitivity reactions to deoxycoformycin

SummaryDeoxycoformycin (dCF) is a promising new antineoplastic agent in the treatment of lymphoid malignancies, particularly hairy cell leukemia (HCL). Skin toxicity in the form of a maculopapular eruption has previously been reported but has not clearly been associated with idiosyncratic reactions. We present five cases of dCF-related hypersensitivity reactions in which additional systemic manifestations indicated an allergic etiology. The value of dCF in treating lymphoid neoplasms suggests that further study of the treatment of these reactions is indicated.

Pyrazole: preclinical reassessment

SummaryPyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893 [1], pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki= 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism [2]. In 1960, pyrazole was identified as being active in preclinical antitumor models [3], which led to preliminary clinical testing [4,5]. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institutes Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model [6]. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960s, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazoles potential role as an anticancer agent.