European Journal of Cancer (1965)最新文献

Two hundred and forty-two patients received 1200 doses of cis-diamminedichloroplatinum (II), generally out of the hospital, at 50 mg/m² every 3–4 weeks. Furosemide and mannitol were given to assure a brisk diuresis when drug was administered, and 2 litres of 0.45% saline-5% dextrose were given over two hours to assure hydration. Azotemia developed after 15 courses (1.3%) in eleven patients (4.5%). Peak serum creatinine was 2 mg/dl in only four patients, and azotemia lasted 12 weeks in only one episode. Incidence of azotemia did not increase with increasing cumulative dose. Two patients had allergic reactions, one died suddenly during drug administration, three had clinically evident hearing loss, and nearly all patients had moderately severe vomiting. Peripheral neuropathy occurred in only 1 of 155 patients not given concomitant hexamethylmelamine.

N-Formyl-leurosine labeled with ¹⁴C in the formyl group was administered to six patients with malignant disease, and the pharmacokinetic behavior of the drug was determined. Chromatographic studies on plasma showed the presence of unchanged drug and 7 metabolites. No metabolites were found in the urine. The plasma decay curve of the unchanged drug was biphasic with half-life values of $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2\alpha </mtext>}}\text{= 18.6 min}$ and $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2\beta </mtext>}}\text{= 4.28 hr}$. Within 72 hr only 30–40% of the radioactivity could be recovered in urine and feces in 5 patients. One patient consumed laxatives during the treatment. In this case 95% of the ¹⁴C-dose was recovered. The contribution made by fecal elimination was 80%.

Significant enhancement of tritiated dCyd suicide occurred when unlabelled dThd was added to cultures of mouse monocytic colony-forming cells. Incorporation experiments supported the suicide experiments in that incorporation of tritiated dCyd into DNA was significantly increased. One hundred micromolar dCyd significantly reduced the radiotoxicity of 0.3 μCi of tritiated dThd; incorporation experiments indicated a dose-related reduction in the incorporation of tritiated dThd into DNA with the addition of 1–100 μM unlabelled dCyd. The addition of 1 μM aminopterin reversed the effect of 100 μM deoxycytidine; viz., incorporation of dThd into DNA was 90% of controls. Aminopterin had a similar effect on deoxyuridine reversal of tritiated dThd incorporation into DNA. Aminopterin had no effect on the reduction of tritiated dThd incorporation into DNA due to the addition of 100 μM unlabelled thymidine. Unlabelled ribonucleosides, Urd and Cyd, did not significantly affect the suicide pattern of tritiated dThd or dCyd when they were added to CFC cultures. Unlabelled deoxyribonucleosides, dThd or dCyd, did not significantly affect the suicide pattern of either tritiated Cyd or Urd when they were added to cultures containing tritiated ribonucleosides. Unlabelled Urd or Cyd was effective in reversing the suicide due to tritiated Urd or Cyd.

The accumulation in rat heart ventricles, the presence of metabolites and the subcellular localization of daunorubicin (DNR), doxorubicin (DOX) and their DNA complexes were investigated. After intravenous perfusion of free DNR or DOX, equal amounts of the drugs are recovered in the heart, whereas after injection of their DNA complexes, the accumulation levels represent 42% (DNR) and 32% (DOX) of those reached with the free drugs. Daunorubicinol and daunomycinone are detected after administration of DNR or DNR-DNA but only trace amounts of metabolites are found with DOX and DOX-DNA. Subcellular distributions of DNR injected as free or DNA complex are similar. Isopycnic and differential centrifugations indicate that DNR could be associated with nuclear DNA and to a smaller extent with lysosomes. By contrast, after injection of free or complexed DOX the drug is almost exclusively associated with the nuclear DNA. The mechanisms by which these drugs are accumulated by the heart and the relation with their cardiotoxicities are discussed.

A controlled clinical trial was carried out on patients with clinical stages I and II of Hodgkin's disease by the E.O.R.T.C. from 1972 to 1976. Three hundred patients with supradiaphragmatic presentation were assigned at random into two groups, one treated by spleen irradiation, the other by splenectomy. All patients received a mantle field irradiation as well as a para-aortic lymph node irradiation. The actuarial survival rates and relapse-free survival rates at five years were, respectively, 90 and 62% in the group treated by spleen irradiation and 90 and 67% in the group splenectomized. The efficiency of the two treatments is therefore identical. In the group submitted to staging laparotomy, all patients received the same treatment without taking into account the results of the splenectomy and of the lymph node biopsy. Of 107 patients without spleen or lymph node involvement 18 relapsed (17%); of 33 patients with spleen involvement 14 relapsed (42%). Relapse in non-irradiated lymph node territories (iliac and inguinal areas) were fifteen-fold more frequent in patients with spleen involvement, whereas extra nodal relapses were about twice as frequent in patients with spleen involvement than in patients without spleen involvement. Patients with mixed cellularity or lymphoid depletion histological types received long term adjuvant chemotherapy either by Vinblastine + Procarbazine or by Vinblastine alone. The 5-year relapse rate was 12% with both chemotherapeutic regimens.

Phase-contrast time-lapse studies on the effect of vincristine (VCR) on HeLa cells have been carried out with different VCR doses (0.0025; 0.005; 0.03 μg/ml) and different incubation times (continuous and 0.5, 1, 3, 12hr). Type and extent of cell damage depend on the applied dose/exposure time relation and on the position of the cells within the cell cycle during VCR treatment. Continuous incubation results in mitotic arrest and subsequent necrosis of all cells entering mitosis, even at VCR concentrations as low as 0.005 μg/ml. The fate of short-term treated cells depends on the time of entry into mitosis. All cells entering mitosis during the first 8 hr after drug removal are lethally or sublethally damaged; later on regular mitoses also occur. Using cinematography it could be shown directly that VCR-arrested mitoses are no longer capable of further regular proliferation. However, VCR does not only cause lethal cell damage, i.e., necrosis after mitotic arrest, but also sublethal damage leading to pathological divisions after mitotic arrest, with descendants not capable of regular proliferation.

Intralesional administration of emulsified trehalose-6,6′-dimycolate was compared to surgery in the treatment of mice with growing intradermal implants of a syngeneic fibrosarcoma. Treatments were given about one month after tumor implantation when a majority of animals so treated had metastatic foci of tumor in the lungs. Mice treated with trehalose-6,6′-dimycolate or by surgery survived significantly longer than untreated mice. Some treated mice were alive and tumor-free six months after tumor inoculation. The differences in cure rates and prolongation of survival between the trehalose-6,6′-dimycolate treated group and the surgically treated group were not statistically significant. Several mice died soon after surgery; no deaths could be attributed to the acute effects of immunotherapy.