Phase I clinical trial with ametantrone (NSC-287513)

Ametantrone is a new aminoanthraquinone derivative that achieves antitumor activity in a large variety of animal models. It is a dark blue dye. In this phase I study, the drug was given as a 30-min i.v. infusion repeated every 2–3 weeks. Nineteen patients were entered into the trial and received a total of 43 courses. All were adult patients with advanced solid tumors, mainly squamous cell carcinoma of the head and neck and nonsmall cell carcinoma of the lung. Sixteen had undergone prior chemotherapy; only one had not been previously treated. The trial was initiated at a starting dose of 10 g/m² and dose levels were escalated up to 180 mg/m². Leukopenia was dose-related, well predictable, rapidly reversible and dose-limiting. At 135 mg/m², the median WBC nadir was 1800/mm³ (1000–4400) and the median PMN was 950/mm³ (460–2240). Among all courses, WBC nadir occurred on median day 12 (8–18) and recovery was seen on medianday 16 (10–29). Thrombocytopenia (< 100,000/mm³) was encountered in two courses. There was no evidence of cumulative myelosuppression with repeated courses. Non-hematological toxic effects were negligible and included stomatitis in one course, minor alopecia in three patients, and questionably drug-related orthostatic hypotension in three patients. Reversible blue skin discoloration was seen in five patients. All patients treated with ≧ 40 mg/m² had dark blue urine for 2 or 3 days. Antitumor activity with response 50% could not be documented. Ametantrone appears to be very well tolerated and easy to handle. Its clinical anticancer potential remains to be determined. A dose-schedule of 135 mg/m² q 2–3 weeks may be recommended for phase II studies in solid tumors.     

Mutiple myeloma resistant to melphalan (NSC-8806) treated with cyclophosphamide (NSC-26271), prednisone (NSC-10023), and chloroquine (NSC-187208).

A prospective randomized study of the effects of two different therapeutic regimens was conducted in 41 patients with multiple myeloma resistant to therapy with melphalan. The results of treatment with cyclophosphamide plus prednisone were compared with those of cyclophosphamide, prednisone, and chloroquine. Chloroquine, which inhibits the repair process of DNA in animals, has reportedly produced responses to alkylating agents to which the animal had been resistant. No significant differences in response to the doses used with either regimen could be found. Toxocity consisted mainly of leukopenia and thrombocytopenia.     

Comparative studies of cyclocytidine (NSC-145668) and cytosine arabinoside (NSC-63878) in mice.

The distribution of cyclocytidine and cytosine arabinoside has been studied in normal BDF mice and in mice bearing 6-day solid L1210 lymphocytic leukemia by whole-body radioautography, bioassay, and radiochemical techniques. Radioactivity was widely distributed throughout the tissues between 15 minutes and 12 hours after a single intravenous dose of either cyclocytidine-2-14C or cytosine arabinoside-2-14C. Whole-body radioautograms demonstrated that for most tissues, cytosine arabinoside-derived 14C was uniformly excreted by 48 hours; cyclocytidine-derived 14C, however, was localized in certain tissues as early as 15 minutes after drug administration and was retained in these sites for 48 hours. Depot loci of 14C included salivary and adrenal glands, fat, cardiac muscle, gastrointestinal tract, and L1210 tumor. The distribution and persistence of cyclocytidine-derived radioactivity is consistent with other reports of toxicity induced by the drug in these tissues. Radiochromatography and bioassay data from BDF mice dosed intraperitoneally with cyclocytidine demonstrated that 65%-95% of the 14C-radioactivity in a number of tissues was the parent compound itself. Thus, cyclocytidine contributed in large measur to the generation of the radioautograms. This study demonstrates that the retention of cyclocytidine in body tissues may serve to effect the sustained release of the deaminase-resistant chemotherapeutic drug from these depot sites and thus prolong cytotoxic levels of drug in tumor tissue.     

Effects of levamisole (NSC-177023) and tetramisole (NSC-102063) in experimental tumor systems.

Levamisole and tetramisole had no antitumor effect against the following transplantable syngeneic murine tumors: L1210 leukemia, P388 leukemia, B16 melanoma, Madison 109 lung tumor, and Lewis lung carcinoma. In the Lewis lung carcinoma system there was no effect on primary tumor growth, metastasis, or survival. Tetramisole had a variable effect on the growth of rhabdomyosarcomas and the survival of BALB/c mice following intramuscular inoculation of Moloney sarcoma virus. In two experiments treatment with tetramisole either prior to or following inoculation of Moloney sarcoma virus increased the number of mice with tumor regression as opposed to progressive tumor growth, incrneased the number of long-term survivors, and prolonged the lifespan of mice that died of tumor. In two further tests neither levamisole nor tetramisole had an effect in this system. In mice immunosuppressed with cyclophosphamide prior to virus inoculation, there was not effect of treatment with levamisole or tetramisole.