Combination chemotherapy with cisplatin, etoposide and gallium chloride for lung cancer: individual adaptation of doses.

Twelve inoperable lung cancer patients were treated with a combination chemotherapy of cisplatinum (CDDP) and etoposide (VP16), as a continuous infusion for 5 days, every 21 days, and with a daily oral administration of GaCl3. Dosages of CDDP and VP16 were adapted in order to obtain an area under the curve (AUC) of 80,000 micrograms l-1.h for plasma total platinum and of 200 mumol.l-1 h for plasma VP16 during each 120 h infusion. GaCl3 was given at the dosage of 400 mg/24h from the time of diagnosis at least until the evaluation after 3 courses of chemotherapy. An objective response was observed in 5 non small cell (NSCLC) lung cancer patients (group 1) and 3 small cell (SCLC) lung cancer patients (group 2). In the other 4 patients with a NSCLC no partial response was noted (group 3). No significant difference in area under the curve (AUC) was noted between the 3 groups, either for plasma total platinum (group 1 = 89,598 +/- 20,843 micrograms l-1.h; group 2 = 88,081 +/- 15,431 micrograms l-1.h; group 3 = 83,820 +/- 13,455 micrograms l-1.h), or for VP16 (group 1 = 227 +/- 41 mumol.l-1 h; group 2 = 217 +/- 29 mumol.l-1.h and group 3 = 211 +/- 30 mumol.l-1.h). The maximal plasma Ga concentrations were 244 +/- 34 micrograms/l in group 1, 112 +/- 57 micrograms/l in group 3 (p less than 0.005) and 243 +/- 132 micrograms/l in group 2. It was then decided to increase the dose of GaCl3 in the further non-responding patients. In 6 responders, 3 additional courses of this combination chemotherapy could have been given without major toxicity, allowing a much more important decrease in the tumor volume in 4 of them. This schedule of treatment should permit the chemotherapy to continue for longer than 6 courses, in order to improve the survival time.

Clinical pharmacology of gallium chloride after oral administration in lung cancer patients.

Pharmacokinetic parameters were determined in 18 lung cancer patients after a single administration of 800 mg/24 h of GaCl3: Cmax = 123 +/- 61 mu/l; Tmax = 5.2 +/- 5.5 h; AUCO-96h = 4690 +/- 3358 micrograms.l-1.h; AUCO - infinity = 6394 +/- 5352 micrograms.l-1.h; T 1/2 beta = 43 +/- 19 h. Serum Ga concentrations at the steady-state (Css) were then determined in these patients after a daily oral administration of 800 mg/24 h of GaCl3 for 15 days: Css = 274 +/- 167 micrograms/l. No correlation was found between Css and the previous pharmacokinetic parameters in each patient. Various doses of GaCl3 were administered daily to 45 patients to correlate Css and dosage. Serum Ga concentrations increased with dosage from 100 to 400 mg/24 h (p less than 0.05), but not with further dosages up to 1400 mg/24 h. The optimal daily dose of GaCl3 in lung cancer patients seems to be 400 mg/24 h. In 2 patients, Ga was assayed after death in tissues. Ga concentrations were more than 10 micrograms/g in metastases, 3.6 +/- 2.9 micrograms/g in the primary tumor and 2.3 +/- 0.9 micrograms/g in the kidney. Due to the lack of renal and hematological toxicities and the significant uptake of Ga by the tumor, GaCl3 can be used orally in conjunction with other cytotoxic agents. We intend to evaluate its efficacy according to a randomized study comparing chemotherapy versus chemotherapy plus 400 mg/24 h of GaCl3.

Ethanol effect on the ionic transfer through isolated human amnion. I. Preventive and antagonistic actions of some nutrients and of their synthetic congeners.

The inhibition of the placental transfer of nutrients was studied in the pathogenesis of the fetal alcohol syndrome. Ethanol reduces the ionic transfer through the human amnion. In this study, the preventive and antagonistic actions of natural nutrients (Mg2+, Ca2+, taurine, homotaurine, gamma-aminobutyric acid) and of their synthetic congeners (Ca2+-taurinate, Ca2+-acetyltaurinate, Ca2+-acetylhomotaurinate) were observed on the amniotic conductance which was modified by ethanol. All the molecules, except Mg, demonstrated protective actions on the fetal side. The effect varied with the molecule and its concentration. An absolute protective effect was obtained on the maternal side with Ca2+-acetylhomotaurinate and Ca2+-taurinate. Some molecules, which have protective actions, had no opposing actions (homotaurine), or inversely (Mg2+), only Ca2+-acetylhomotaurinate exhibited both a preventive and an opposing action against ethanol. These results show the interest of studying synthetic molecules for prevention of fetal alcoholism.

Comparative studies of Ca N-acetylhomotaurinate and Ca N-acetyltaurinate. I. Effects on the ionic transfer through the isolated human amnion.

The effects of two taurine and homotaurine derivatives (Ca N-acetyltaurinate: ATACa and Ca N-acetylhomotaurinate: AOTACa) were studied on the ionic transfer through a membranous model: the human isolated amniotic membrane. The ionic transfer was evaluated by measurements of the various components (cellular and paracellular) of the total conductance across the membrane. AOTACa influenced all the components of the total ionic conductance without flux ratio modifications and the general action scheme was a biphasic effect: decrease conductance with low concentrations and increase conductance with high concentrations. This effect might be important in the case of lower or higher supplementation. ATACa only interfered with some conductance components and this action was predominantly monophasic (decreased or increased conductance). This study indicates differential actions between two closely related molecules on a membranous model.

Comparative studies of Ca N-acetylhomotaurinate and Ca N-acetyltaurinate. II. Preventive and opposing actions of the acute ethanol depletive effect on the ionic transfer through the isolated human amnion.

Ethanol reduces the ionic paraplacental transfer through the human amnion. This effect is exerted on the cationic paracellular pathway, the coupling between two adjacent epithelial cells, the monovalent cation pump and the antiport system. In this study, the preventive and opposing actions of two taurine and homotaurine derivatives (Ca N-acetyltaurinate: ATACa, Ca N-acetylhomotaurinate: AOTACa) were observed. One the maternal side, ATACa and AOTACa demonstrated protective actions on cationic paracellular pathways and on the Na/K-ATPase pump with AOTACa only. On the fetal side, the effect of ATACa was limited to the sodium paracellular pathway. This effect was total at 5 mM. On the maternal side, ATACa and AOTACa exhibited an opposing action on the same components of the conductance. But on the fetal side, ATACa increased the ethanol effect and AOTACa exerted an antagonistic effect on the cation pump only. These results indicate that two closely related molecules may have different effects on a membranous ethanol model.

Effect of magnesium supplement in a biological medium (milk) on multiple ionic exchangers in a human membrane.

The effects of magnesium supplement in a biological medium (milk) diluted in a survival medium (1/20 dilution in Hanks' solution) have been studied on the multiple ionic exchangers in a human membrane, the amniotic membrane, which is a leaky and asymmetrical membrane. In normal milk, the Ca/Mg molar ratio (MR) is equal to 6.0. In this study, this ratio has been modified to between 0.36 and 6.0, with particular attention to MR values of 0.36, 0.6, 1.0, and 2.0. The transamniotic conductance, Gt, is a function of the Ca/Mg MR: Gt decreases when the MR increases from 0.36 to 6.0, with an inflexion point to 0.7. In the human amnion, Gt is the sum of three paracellular components (Gp) and nine cellular components (Gc). The addition of normal milk (MR = 6) or magnesium-supplemented milk (MR = 0.36, 0.6, 1.0 or 2.0) induces variation in 2 Gp (GpNa and GpK) and three cellular conductances (Na+ and K+ channels and Na/Mg exchanger). Among the MR values studied, MR = 0.36 increased all five components. These data show the relationship between magnesium and milk components and the cellular targets of magnesium supplements and define the best Ca/Mg molar ratio in the biological medium.