Contact allergy to aziridine paint hardener.

A painter experienced an extensive dermatitis when exposed to a paint primer (undercoating) used to protect wood siding. The primer was an acrylic emulsion with a polyfunctional aziridine added as a self-curing cross-linker or hardener. The polyfunctional aziridine cross-linker was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). Our patient reacted to the cross-linker and also reacted to TMPTA, which is present in excess in the cross-linker. He also cross-reacted to pentaerythritol triacrylate (PETA). Both TMPTA and PETA can be used in the production of aziridine hardeners and both are well known as sensitizers in radiation-dried acrylic printing inks and coatings.

Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA.

Tris (1-aziridinyl) phosphine oxide (TEPA) and tris (1-aziridinyl) phosphine sulfide (thio-TEPA) induced base pair mutations in the Ames mutagenic assay. Thio-TEPA required metabolic activation while TEPA was active without metabolic activation. Growth of a human vaginal carcinoma (A431), a human breast carcinoma (MDA-MB-231), and a human cervical carcinoma (HeLa) were inhibited in soft agar in vitro at concentrations which induced mutagenesis in the Ames Assay. A fourth line, JEG choriocarcinoma, was sensitive to the antigrowth properties of both drugs at concentrations below that which induced mutagenesis. These data suggest that as more antineoplastic agents become available, and as mean survival times increase, knowledge of the relative in vitro sensitivity of a patient's neoplasm to a specific antineoplastic drug (i.e., dose required for growth inhibition) as a function of its mutagenic index might be useful for prediction of clinical remission, as well as the risk of secondary neoplasm induction.

Anaphylactic reactions to diaziquone.

Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on six cases of hypersensitivity attributable to diaziquone. In five patients an acute reaction characterized by hypotension, bronchospasm, and urticaria was observed. In one patient a delayed urticarial rash was noted. Resolution was rapid in all patients but one, who responded to standard treatment over a period of hours. No reaction was fatal. Approximately 2000 patients have been treated with diaziquone in clinical trials sponsored by the National Cancer Institute. It is suggested that the reaction may not be to the drug itself but to the vehicle (dimethylacetamide) in which diaziquone is formulated. Studies to elucidate the relative contribution of drug and vehicle are warranted.

[Fundamental studies on intravesical instillation of carboquone for treatment of urinary bladder tumors--on the effects of intravesical instillation of carboquone in normal beagle dogs].

The effects of intravesical instillation of Carboquone at the clinically used doses of 5 and 10 mg on the normal mucosa of female beagle dogs was compared with that of 10 mg Mitomycin C used as the control drug. Intravesical instillation for 48 hours of 10 mg carboquone/20 ml phosphate buffer solution (PBS) after bilateral cutaneous uretrostomies produced severe inflammatory changes in all layers of the bladder wall. However, no secondary effects were observed in blood laboratory examinations or histological examinations of the whole organ after autopsy. Phosphate buffer solution produced no remarkable secondary effects in animals. Five milligrams carboquone per 20 ml PBS was instilled intravesically once a week for 3 weeks in normal animals. Cystoscopically , the bladder mucosa recovered normally. Blood laboratory examinations showed no abnormal results, but the bladder epithelium had regenerative epithelial hyperplasia and slightly inflammatory changes in the submucosal layers. Two of the three control animals given instillation of 10 mg of Mitomycin C/20 ml PBS had slight leucopenia at 7 days after the last intravesical instillation, but leucocyte count was normal at the end of the experiment. Cystoscopic and histological examination of the epithelium of the urinary bladder revealed severe inflammatory changes in 2 of the 3 animals.

Diaziquone (AZQ).

Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. Parent diaziquone appears to have a t1/2 beta of approximately 30 min. The drug is rapidly and widely distributed to tissues as evidenced by a t1/2 alpha of approximately 1-3 min and a volume of distribution exceeding that of total body water. In addition, it rapidly penetrates the central nervous system, reaching peak concentrations (30-50%) of corresponding plasma levels) in approximately one hour. Diaziquone is rapidly and extensively metabolized by the liver. Diaziquone is a potent marrow suppressive agent inducing significant degrees of leukopenia, granulocytopenia, and thrombocytopenia in humans. Thrombocytopenia is often severe. Although myelosuppression is for the most part dose related, many patients had significant toxicity even at lower doses. Most investigators have attributed this to the extent of prior therapy. Diaziquone demonstrates a very steep dose-response relationship. Myelosuppression was the dose-limiting toxicity in all phase I trials. No nonhematologic dose-limiting toxicity has been identified to date. In phase I and preliminary phase II trials, diaziquone has demonstrated activity against primary brain tumors. Little activity has been seen in other tumor categories. It should be noted, however, that all studies to date have been carried out in heavily pretreated patients. Because of the broad spectrum of antitumor activity in experimental murine tumors, the lack of nonhematologic dose-limiting toxicity, the ability of this drug to attain significant levels in the central nervous system, and the activity of the drug in primary brain tumors, further studies examining its role in the management of patients with cancer are warranted. These studies should be conducted in patients who have had little or no prior therapy in order to better evaluate the efficacy of the drug.

Phase I clinical trial of (NPAz2)2NSOAz: 'SOAz'.

(NPAz2)2NSOAz ('SOAz') is the first of a new class of cytotoxic agents containing an inorganic heterocyclic ring system to enter clinical trial. It was used to treat 31 patients with advanced cancer by IV infusion over 30 min on days 1, 2, 3, and 4 of a 21-day cycle, which was postponed if necessary to allow for hematological recovery. A total of 46 courses evaluable for toxicity was given and the tumor response was evaluable in 21 patients. Seven dose levels, ranging from 25 mg/m2 to 300 mg/m2, were studied, with three to six patients at each level. The only major toxicity was myelosuppression, especially thrombocytopenia, which was dose-limiting. Platelets decreased from the 14th day onward, with a nadir 4-5 weeks after administration. Leukopenia was less predictable and reached a nadir 3-5 weeks after administration. In most patients recovery was complete after 6-9 weeks. Myelosuppression was clearly cumulative in succeeding courses and proved irreversible in three patients. Anemia also occurred, but otherwise SOAz was remarkably well tolerated. There were no responses and no therapy-related deaths. The highest tolerated dose for patients who had received no or only minor chemotherapy prior to treatment with SOAz was 300 mg/m2, and that for heavily pretreated patients, 175 mg/m2. Because of cumulative myelotoxicity phase II studies with SOAz are not recommended.

Phase I study of SOAz.

SOAz, an inorganic cyclic derivative, was given as a single iv injection through one cycle in a phase I trial. Dose-limiting toxic effects noted were neutropenia and thrombocytopenia occurring at doses greater than or equal to 220 mg/M2 in patients with prior myelosuppressive treatment. The time to nadir for blood cell counts was long, as well as the time to recovery, so cumulative toxicity could be suspected. No other significant toxicity was noted. In patients with measurable volume, no significant antitumor responses were seen. For further study, the dose of 220 mg/m2 every 6-8 weeks according to hematologic restoration is recommended.

Phase I study of aziridinylbenzoquinone (NSC 182986).

A phase I clinical study of aziridinylbenzoquinone (AZQ) was conducted in 33 patients with various types of advanced solid tumors to evaluate its toxicity and efficacy. The initial dose of 0.5 mg/m2/day X 5 days repeated at 3-week intervals was progressively increased to a maximum dose of 12.0 mg/m2/day. Thrombocytopenia was the dose-limiting toxic effect; it was delayed, cumulative, and occurred more often in patients with extensive prior chemotherapy and radiotherapy. Anemia was common and severe at higher doses, while nausea and vomiting were observed only in some patients and usually were mild. Objective tumor regressions were observed in 3 of 17 patients who received biologically active doses of AZQ, i.e., 6 mg/m2/day or higher. Minor responses were seen in two of three patients with malignant melanoma and in a patient with adenocarcinoma of unknown primary. The recommended starting dose of AZQ for good-risk patients is 8.0 mg/m2/day X 5 days for phase II studies.

Pulpal response to a temporary crown and bridge material in ferret teeth.

The histological effects of a temporary crown and bridge material (Scutan) on the pulp of canine teeth of ferrets was investigated at time intervals up to 6 months. After 24 h a moderate to severe pulpal response was observed which persisted up to 6 months. A case of contact sensitivity to Scutan is reported.