Yvon Kenis

Phase I clinical study of 9-hydroxy-2N-methyl-ellipticinium acetate (NSC-264137) administered on a 5-day i.v. schedule☆

Twenty-three patients with advanced solid tumors received 9-hydroxy-2N-methyl-ellipticinium acetate at a single daily i.v. dose of 15-80 mg/m2 for 5 consecutive days, repeated every 3 weeks. One partial and one minor response were achieved in two patients with breast cancer. Dryness of the mouth was dose-related and dose-limiting. Local phlebitis was also dose-related and frequently severe at the highest dose levels. Other non-hematologic toxic effects were essentially mild to moderate and included nausea, vomiting, diarrhea, stomatitis, fever, weakness, transient renal and hepatic impairment, alopecia and chest pain. Minimal myelosuppression was encountered. It appears that 60 mg/m2/day is the maximum tolerated dose with a five-day schedule. According to our findings, this schedule does not seem to offer any advantage over the previously tested weekly administrations.

Combination chemotherapy with 1-(2-chloroethyl-3-cyclohexyl-1-nitrosourea) (CCNU), vincristine and methotrexate in primary and metastatic brain tumors—A preliminary report

Abstract Thirty-eight patients, 15 with recurrent primary brain tumors, 8 with breast carcinoma and 15 with lung carcinoma brain metastases were treated by a combination of 1-(2-chloroethyl-3-cyclohexyl-1-nitrosourea) (CCNU): 100 mg/m2 every 6 weeks; vincristine: 2 mg/m2 and methotrexate: 24 mg/m2 both given once a week for 4 weeks and subsequently once every 4 weeks. Dexamethasone: 10 mg/m2 per day was initiated concomitantly with chemotherapy and administered for 4 weeks. Chemotherapy was well tolerated. Objective remission, defined as clinical improvement present 6 weeks after complete discontinuation of dexamethasone and lasting for 4 weeks or more, was observed in 11 patients: 6 with primary brain tumors, 4 with breast carcinoma and 1 with lung carcinoma brain metastases. In 7 patients, the remissions were characterized by a remarkable functional recovery. EEG and brain scan appeared both as useful complementary examinations in the estimation of tumor size modifications.

In vitro chemosensitivity of brain tumors to cisplatin and its analogues, iproplatin and carboplatin

SummaryThe human tumor stem-cell assay was used to investigate the in vitro chemosensitivity of 27 evaluable samples to cisplatin and its analogues, iproplatin and carboplatin, as well as to BCNU, teniposide, vindesine, and dibromodulcitol. All agents exhibited some antitumor activity with the exception of dibromodulcitol (zero response out of 19 evaluable samples). Vindesine, BCNU, and carboplatin were the three most active compounds, with response rates of 29%, 23%, and 22%, respectively. There was a lack of complete cross-resistance between carboplatin and cisplatin as well as between carboplatin and BCNU. Our data suggest that clinical studies with carboplatin and combinations of vindesine plus cisplatin and its analogues may be worthwhile.

Prognostic value of the superior vena cava syndrome as the presenting sign of small cell anaplastic carcinoma of the lung

Abstract In a series of 45 patients with small cell anaplastic carcinoma of the lung with disease limited to one hemithorax, 15 of them presented at the time of diagnosis a superior vena cava syndrome. Both groups were similar in terms of response rate and survival. Superior vena cava syndrome is not an independent prognostic factor in small cell carcinoma of the lung.

Phase I trial with 4'-deoxydoxorubicin (esorubicin)

Summary4′-Deoxydoxorubicin is a new anthracycline derivative. Experimentally, the drug shows efficacy against doxorubicin-resistant malignancies and, as compared to the parent compound, it has reduced potential for heart damage. This Phase I trial was conducted with a single dose intermittent schedule. 4′-Deoxydoxorubicin was given by rapid i.v. administration at doses of 20, 30, 35 and 40 mg/m2. A total of 25 adult patients with a variety of solid tumors received a median of two courses (1–4). Leukopenia was dose-related and dose-limiting. Occasionally severe thrombocytopenia was also encountered. Nonhematological toxic effects were mostly mild to moderate and were qualitatively similar to those commonly reported with doxorubicin. The frequency of local reactions was apparently increased but the incidence of alopecia and gastrointestinal distress was noticeably lower. There were no acute or chronic drug-induced cardiac effects. Antitumor activity was suggested in a patient with a carcinoma of the cardia. For Phase II trials, doses of 35 and 30 mg/m2 every 3–4 weeks may be recommended in good-risk and poor-risk patients, respectively.

Effect of daunorubicin, carminomycin, idarubicin and 4-demethoxydaunorubicinol against human normal myeloid stem cells and human malignant cells In vitro

The cytotoxic effect of daunorubicin, carminomycin, idarubicin and the major metabolite of idarubicin in man, 4-demethoxydaunorubicinol, was investigated in a human normal progenitor myeloid stem cell assay and in a human tumor stem cell assay. Against normal myeloid progenitor cells, idarubicin and carminomycin were equally potent; both agents were significantly (P less than or equal to 0.01) more potent than daunorubicin. Idarubicin was approx. 2.5 times more potent than 4-demethoxydaunorubicinol. Against malignant tumor cells, 50% cell kill after exposure to idarubicin was observed in four out 24 samples; this inhibition occurred at a drug concentration of 0.1 micrograms/ml. Two of the samples sensitive to idarubicin were also sensitive to 4-demethoxydaunorubicinol at a concentration of 0.1 micrograms/ml. Overall, idarubicin was active against two out of six ovarian carcinomas and against one out of three breast carcinomas. Our data confirm that 4-demethoxydaunorubicinol may play a role in the biological activity of idarubicin.

In vitro chemosensitivity testing of flavone acetic acid (LM975; NSC 347512) and its diethylaminoethyl ester derivative (LM985; NSC 293015)☆

The antitumor effect of flavone acetic acid, LM975, and its diethylaminoethyl ester derivative, LM985, was studied in four human malignant cell lines [WiDr, a colon carcinoma; LICR (LON) HN-3, a tongue carcinoma; MCF7, a breast carcinoma; K-562, a leukemia] using a colorimetric assay based on the reduction of dimethylthiazol-2-yl-diphenyltetrazolium. The cell lines were exposed continuously for 4-6 days to drug concentrations ranging between 0.1 and 500 micrograms/ml. For LM975, the concentrations inhibiting the growth of the various cell lines by 50% were 200 +/- 10, 97 +/- 7, 171 +/- 16 and greater than 500 micrograms/ml for LICR (LON) HN-3, WiDr, MCF-7, and K-562, respectively. The corresponding concentrations for LM985 were 151 +/- 3, 36 +/- 4, 86 +/- 3 and 140 +/- 18 micrograms/ml, respectively. The difference between LM985 and LM975 was statistically significant for the WiDr and LICR (LON) HN-3 lines. We also evaluated the cytotoxic activity of the two agents on normal human marrow myeloid progenitor cells in a colony-forming assay. Continuous exposure to the drugs gave a dose-dependent inhibition. The concentrations inhibiting the growth by 50% were 76 +/- 31 micrograms/ml for LM975 and 134 +/- 41 micrograms/ml for LM985. One hour incubation with either compound had no toxic effect on the myeloid progenitor cells. In conclusion, LM975 and LM985 do not appear to have a specific cytotoxicity for tumor cells. Our results indicate that, in vitro, toxicity on bone marrow myeloid progenitor cells is concentration dependent. Considering the low plasma concentration found in man after i.v. administration of LM985, our observations correlate well with the absence of drug-induced myelosuppression in patients.

Phase I clinical trial with alpha 1,3,5- triglycidyl-s-triazinetrione (NSC-296934).

Abstract 1,3,5 -Triglycidyl- s -triazinetrione is a triepoxide derivative with attractive antitumor properties in mice. In this phase I trial, the drug was given as an i.v. infusion over 30 + min repeated every 2–3 weeks. The trial was initiated at a starting dose of 33 mg/m 2 and doses were escalated up to 2,000 mg/m 2 . Local thrombophlebitis was dose-limiting and apparently dose-related. Other toxic effects were mild to moderate and consisted of nausea, vomiting, leukopenia and hair loss. More favorable formulations or schedules of administration are needed before testing this new agent in phase II trials.

Adjuvant immunotherapy by levamisole in resectable lung cancer: a control study.

Abstract Since 1976, a double blind study has been conducted to assess the value of levamisole as adjuvant treatment to surgery for non-small cell carcinoma of the lung. Fifty-one patients were evaluable with a minimal follow-up period of 1 yr. No difference could be observed between the two groups in the duration of the survival and of the disease free survival. In cases of complete resection without any lymph node involvement, an increase of the free interval was observed. This was not statistically significant.

Clinical Studies with a THC Analog (BRL‐4664) in the Prevention of Cisplatin‐Induced Vomiting

Abstract: BRL‐4664, a THC analog, has been administered to 23 patients at a dose of 10 or 15 mg repeated twice. All patients were on cisplatin therapy, and 16 of them had experienced severe vomiting during the previous course of cisplatin. There was a statistically significant difference between the group with prior cisplatin therapy and without prior therapy in terms of number of vomiting episodes, emphasizing the role of conditioned reflexes. The dose of 15 mg administered before and twice after the infusion of cisplatin was well tolerated. Only minor side effects were observed.