5 ' -Deoxy-5f luorour id ine (5 ' -dFUrd) is a new ant ineoplast ic agent which possesses a higher therapeut ic index in several experimental tumors compared to other f luoropyr imidines. During a Phase I trial, 5 ' -dFUrd, 1 to 15 g / s q m / w e e k , was administered to patients as a 25to 35-min i.v. infusion. Plasma kinetics and metabol ism of 5 ' -dFUrd were investigated. The unmetabol ized drug was measured by a h igh-per formance liquid chromatography assay. 5-Fluorouraci l and 5 ,6-d ihydrof luorouraci l , the two detected plasma metabolites, were quantitated by a gas chromatography-mass spect rometry methodology with a detect ion limit of 0 .07 ffM for both metabolites. The disposit ion of 5 ' -dFUrd in humans at therapeut ic doses fol lowed a nonl inear kinetic process. Plasma concentrat ions of 5-f luorouraci l generated in v ivo represented approximately 6% of 5 ' -dFUrd concentrat ions and the 5-f luorouraci l half-life ranged from 8.8 to 27.1 rain. High plasma values of 5, 6d ihydrof luorouraci l (14.5 to 30 ffM) were observed in patients, indicating the importance of this pathway in humans.

One hundred forty-four heavy-smoker (125 males, 19 females) volunteers with at least 15 packet-year of smoking experience (number of daily packets of cigarettes X number of years of smoking) underwent bronchoscopy with systematic biopsies in ten sites of the bronchial tree. No morbidity was related to the fibroscopy procedure. Each biopsy was cut into ten sections and an index of metaplasia (IM) was calculated: IM = number of sections with epidermoid metaplasia/number of sections examined X 100. A highly significant statistical correlation was observed (P = 10(-4)) between the IM and the amount of cigarettes smoked (slope of the curve: 0.23). Sex appeared to play an important role in the incidence of metaplasia, since 84% of the examined females had an IM less than 15% versus 48% of the males (P adjusted for individual tobacco consumption in packet-years less than 0.01). Early study of HLA phenotype (locus A) failed to detect a link between HLA and risk of tobacco-induced epidermoid metaplasia.

Cis-dichloro-trans-dihydroxy-bis(isopropylamine)platinum IV (CHIP) is a second-generation cis-platinum (DDP) derivative with an octahedral conformation of the platinum complex, far more water-soluble than DDP. Tests in numerous murine tumor systems demonstrate a spectrum of activity similar to that of DDP. A phase I study of CHIP using 5 consecutive daily 1-hour infusions without pretreatment hydration or diuretics was completed at Hospital Paul-Brousse, Villejuif, France. 16 patients received a total of 28 courses of CHIP. In 11 of them hematologic toxicity could be assessed. The starting dose, 20 mg/m2/day X 5, was increased to 30, 45 and 50 mg/m2. There was neither renal nor neurotoxicity. Nausea and vomiting were constant but usually mild or moderate. No diarrhea was seen. Myelosuppression was dose-limiting with a mean polymorphonuclear cell (PMN) count nadir of 2.4 X 10(3)/mm3 (range 1 X 10(3)-3 X 10(3)/mm3) and a mean platelet count nadir of 110 X 10(3)/mm3 (range 60 X 10(3)-180 X 10(3)/mm3) at the recommended dosage of 45 mg/m2/day X 5. The drug should be given every 6 weeks because of the late platelet nadir. A total of 13 patients are evaluable for efficacy. One histologically documented complete response lasting more than 12 months was observed in a patient with an ovarian carcinoma.

40 voluntary heavy smokers (over 15 packets-years) were selected for and have completed a six months etretinate treatment on the basis of an index of metaplasia (IM) greater than 15% determined according to the following procedure: bronchoscopy with systematic biopsies in 10 sites of the bronchial tree. Each biopsy was cut into 10 sections and an IM was calculated: (Formula: see text). Etretinate, a retinoid derivative, was given orally at the daily dose of 25 mg, at the end of which they underwent a second fibroscopy protocol. A highly significant reduction of IM (p = 10(-5)) was observed after 6 months of treatment for those of the patients who maintained their smoking habits during treatment. Besides, the 4 patients who stopped smoking while under treatment and are excluded from the statistical analysis, all had a complete regression of metaplasia at the second fibroscopy. No morbidity was due to etretinate or fibroscopy. Etretinate significantly reduces potentially precancerous bronchial epidermoid metaplasia in heavy smokers. Its association with smoking arrest may induce a rapid restoration of bronchial epithelium to normal.

5'-Deoxy-5-fluorouridine (5'-dFUrd) is a new antineoplastic agent which possesses a higher therapeutic index in several experimental tumors compared to other fluoropyrimidines. During a Phase I trial, 5'-dFUrd, 1 to 15 g/sq m/week, was administered to patients as a 25- to 35-min i.v. infusion. Plasma kinetics and metabolism of 5'-dFUrd were investigated. The unmetabolized drug was measured by a high-performance liquid chromatography assay. 5-Fluorouracil and 5,6-dihydrofluorouracil, the two detected plasma metabolites, were quantitated by a gas chromatography-mass spectrometry methodology with a detection limit of 0.07 microM for both metabolites. The disposition of 5'-dFUrd in humans at therapeutic doses followed a nonlinear kinetic process. Plasma concentrations of 5-fluorouracil generated in vivo represented approximately 6% of 5'-dFUrd concentrations and the 5-fluorouracil half-life ranged from 8.8 to 27.1 min. High plasma values of 5,6-dihydrofluorouracil (14.5 to 30 microM) were observed in patients, indicating the importance of this pathway in humans.

Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon alpha (IF alpha). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with a rising dose in the same patient from cycle to cycle, if tolerance permits, from 1.5 to 6 X 10(6) units daily. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who had previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10(6) units daily. Tumor mass reduction was seen in only three patients, but significant decrease in peripheral lymphocytosis was seen in 7 patients sustained in the continuous treatment group with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed, in this population of patients, a very good correlation between NK cell activity and clinical response. Further studies are warranted to determine the best modalities of treatment as well as the population of patients likely to benefit from it, and the possible special respective indications of IF, and of the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.

Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon a (IF a). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with dose escalation in the same patient from cycle to cycle from 1.5 to 6 X 10(6) units daily, if tolerated. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who has previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10 units daily. Tumor mass reduction was seen in only three patients. However, a significant decrease in peripheral lymphocytosis was seen in 7 patients who were sustained in the continuous treatment group; with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed a good correlation between NK cell activity and clinical response, in this group of patients. Further studies are warranted to determine the best modalities of treatment, the population of patients likely to benefit from such treatment, the possible special respective indications of IF, and also the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.

18 patients with malignant gammapathies (16 with myeloma and 2 with Waldenström's disease) were treated with human fibroblastic Interferon (beta IF). This was administered i.v. 6 X 10(6) units weekly (7 patients) or 3 X 10(6) units twice weekly (11 patients). during at least 3 months if tolerated. Treatment was discontinued because of side effects in three patients. Reduction of the M component, by at least 25% from the initial value, was obtained in 3 patients. In one case the disappearance of a urinary Bence Jones protein was observed. In 4 cases, there was a significant reduction of bone marrow infiltration by plasma cells. In 5 cases, major alleviation or disappearance of bone pain was observed. Duration of treatment seemed to be an important factor for activity. Immune monitoring with currently available tests, mainly natural cytoxicity, yielded no correlation with therapeutic effect in these patients. This preliminary study demonstrates the effect of fibroblastic Interferon in myeloma. However, further studies are necessary to determine the population of patients most likely to benefit from treatment, the best modalities, possible special indications, dose schedules and duration of treatment. As it is not myelosuppressive it could be indicated in the frequent situation of advanced myeloma with bone marrow failure, contra-indicating combination chemotherapy.

Six patients with pure meningeal relapse of acute lymphoblastic leukemia (ALL) (5 patients) or leukemic lymphosarcoma (LS) (non Hodgkin's lymphoma) (NHL) (1 patient) were treated with intrathecal (I.T.) human fibroblastic interferon (IF beta), one vial (1.3 million units) every other day or every day up to remission or failure. Tolerance was excellent in all six patients with no local or general side effects. 5 patients had no improvement of their meningeal blast infiltrations after 5 to 8 injections and were given IT chemotherapy. The sixth patient achieved a complete remission (CR) after 11 injections, and was maintained in CR for eleven months under systemic and IT chemotherapy. IF cannot be proposed as standard treatment for meningeal leukemia, but we may be able to select a population of patients in which it could be indicated. Its combination with methotrexate and arabinoside cytosine, the two agents used IT which are S-dependent, has to be studied for a possible potentiation. Moreover, its good tolerance would permit its use in severe meningeal viral diseases.

Vitamin A and its derivatives, so-called retinoids, can prevent squamous metaplasia induced not only by vitamin A deficiency but also by carcinogenic hydrocarbons. An aromatic retinoid, such as ET1, has been shown to prevent chemically induced papillomas in mice and to amplify certain immunologic reactions. Heavy smokers, 106 volunteers, were submitted to fibrobronchoscopy with bronchial biopsies. An index of metaplasia (IM) was calculated on the basis of microscopical examination of a total of 9,633 sections of 1,010 biopsies. Despite the subjectivity of the estimates of cigarette consumption, this was significantly (P less than 0.02) and positively correlated to the IM. Eighty-five percent of the women had a low IM as compared to only 42% of the men (P less than 0.01), although there was no significant difference in the reported cigarette consumption. Fifty-two subjects had an IM greater than 15% and were given 25 mg ET1 orally daily for 6 months. The bronchoscopy was repeated in 30 patients following completion of the 6-month treatment. The IM was significantly (P less than 0.01) reduced after treatment.

Fifty-seven patients with digestive tract tumors or metastatic tumors of unknown origin were treated in a phase II trial with RFCNU [chloro-2-ethyl-1-ribofuranosyl-(isopropylidine-2′-3′-paranitrobenzoate-5′)3-nitrosourea] administered on a two-day schedule. Doses were based on the results of a phase I trial, and ranged from 300 to 350 mg/m2. When hematological tolerance was excellent, the dose was escalated to 570 mg/m2. In cases of documented bone-marrow intolerance, we decreased the total dose to below 300 mg and even gave only 150 mg/m2 to one patient. Courses were repeated every month. Three complete remissions (CR) and five partial regressions (PR) were achieved among 57 patients available for assessment of response. The overall rate of major responses (CR + PR) (PR being regressions superior to 50%) was 14%, with a median duration of 9 months. These major responses included 4 cases of liver metastases (including 2 CR) and 3 lung metastases of colorectal carcinoma (one CR). The responses were obtained at doses in excess of 275 mg/m2. We also obtained 30% CR + PR in the case of a metastasis of unknown origin. This above evaluation is severe because it only reports major responses according to the WHO-EORTC-NCI recommendation. We also mention in complement 12% responses inferior to 50% in colorectal cancers, one in a stomach carcinoma, one in a hepatoma and 15% more in metastasis of unknown site primary tumors. The hematological toxicity was mild. It consisted of thrombocytopenia 18%, which was only dose-limiting in 3 patients (6%) previously treated with other nitrosoureas. Leukopenia with white cell counts of 1500/mm3 was rarely observed. In 32 previously untreated patients, no correlation was found between hematologic toxicity and the number of cycles administered. Nausea and vomiting were noticed in 14% of patients. These results indicate that the efficacy of RFCNU for digestive tract tumors is at least comparable and probably slightly superior to that of other nitrosoureas. Adverse reactions, and mainly with hematological toxicity, were less marked that those observed with BCNU, CCNU or MeCCNU and do not appear to be cumulative.