European Journal of Cancer (1965)最新文献

Cerebrospinal fluid (CSF) putrescine (Pu) levels are extremely useful measures of active tumor growth in patients harboring medulloblastoma but not in patients harboring most supratentorial malignant gliomas. This study was designed to determine the diffusion coefficient (D) for Pu in cat brain and the capillary permeability coefficient (P_c) in rat brain to explain the failure of supratentorial gliomas to manifest a consistent increase in CSF Pu with progressive tumor growth. The P_c for Pu was found to be greater than the P_c for urea, while the apparent brain D for Pu was lower than that for urea. This implies that Pu crosses capillaries and enters cells more rapidly than urea, which would reduce the amount of Pu that might ultimately reach the CSF by diffusion from tumor. These data explain why CSF levels of Pu are correlated best in medulloblastoms—generally located adjacent to the CSF pathways—and why levels are correlated least in malignant supratentorial gliomas—usually located within the brain hemispheres, from which diffusion to the ventricles and into the CSF would be difficult.

A generalized acute myeloid leukemia was induced in inbred Sprague-Dawley rats by intravenous injection of chloroleukemia cells. In the bone marrow, colonization by blast cells was observed soon after transplantation and at the end of the disease leukemia cells accounted for about 70% of the whole cell population. In the peripheral blood, erythrocyte and platelet counts decreased late in the disease, while from day 5 onwards there was a progressive increase in the leukocyte count owing to blast cells released into the bloodstream. Spleen, liver and central nervous system were also involved in the disease. The survival time of transplanted animals correlated with the number of cells injected: after transplantation of 2 × 10⁷ chloroleukemia cells survival time was 8.3 days, and with each 10-fold reduction of the inoculum survival time increased by about 2.5 days. The data presented show that Shay chloroleukemia mimics some features of human acute myeloid leukemia and possesses a predictable and highly reproducible growth rate, thus providing a further useful experimental model.

The oestrogenic and antioestrogenic activity of potential alkylating derivatives of tamoxifen and oestradiol 3-methyl ether have been compared with tamoxifen and oestradiol benzoate in the immature rat. Although all the tamoxifen derivatives demonstrated an ability to inhibit the binding of [³H]oestradiol to rabbit or rat uterine oestrogen receptors in vitro, none of the compounds was as potent as tamoxifen in tests for antioestrogenic activity in vivo. The potential alkylating derivatives of oestradiol 3-methyl ether were not antioestrogenic. The properties of all the compounds in vivo did not suggest irreversible effects upon the uterus. Since the assays in vitro did not predict activity in vivo the results indicate that only agents with very high affinity for the oestrogen receptor that do not potentially require metabolic activation may be useful in vivo.

The response of intramuscular Lewis Lung carcinoma (3LL) and its pulmonary metastases to graded doses of adriamycin (AM) was investigated in C57B1/6 mice given the drug i.v. 11 days after tumor implantation and the effect was quantitated by recording tumor or metastases weight at various intervals after treatment. In the same experimental tumor model the distribution of AM in primary and secondary neoplasms was studied by a fluorimetric procedure. The results indicate that, compared to the primary 3LL implant, AM has a much more pronounced effect on a percentage basis on the lung nodules, where the drug reaches 3–5 times the levels in the intramuscular tumor. In order to clarify the role of this better drug availability in determining the higher response at the metastic site, the experimental correlation law between AM amount (peak level or area under the concentration versus time curve, AUC) and the drug effect (the smallest ratio of mean tumor or metastases weights in treated to untreated animals) was investigated for both primary and secondary tumors, and the concentration-response curves thus constructed were compared with the dose-response curves. If the effect is related to drug concentration, there is definitely less difference between the response of intramuscular 3LL and its metastases to AM and it even disappears at certain concentrations. The ed₅₀ for the primary tumor is 10 times higher than for the lung nodules if derived from the dose-response curve, and only 2–3 times higher if derived from the concentration-response curve. Moreover, the lack of linear relationship and the biexponential correlation between the variables of effect and dose or peak concentration or AUC, either for the intramuscular or pulmonary 3LL, indicates that the effect does not increase proportionally to the drug amounts, suggesting that other factors beside AM concentration may contribute to the better drug response at the metastatic site.

The prospective screening program at the Division of Cancer Treatment, National Cancer Institute, has now been in operation for several years and is making steady progress in the identification of new synthetic compounds and natural products of potential interest for the clinic. Data are presented on four categories of drugs that have been tested in the new screening panel: (a) clinically established antitumor agents; (b) new drugs and drugs for which there is renewed clinical interest based on activity in the new screen and previously inadequate clinical trial; (c) drugs in the initial phases of clinical trial; (d) compounds in development. An analysis of the data is presented, taking into account a series of important questions that are being addressed prospectively to the new screen. Although the ability to provide definitive answers must await feedback from clinical testing of compounds recommended by the screen, some generalizations appear to be emerging, and these are discussed. A comparison is made of the activity of drugs in the treatment of human tumors growing in two sites, subcutaneously and under the renal capsule. The subrenal capsule model appears to be somewhat more sensitive to drugs than the subcutaneous model and may provide certain advantages for initial panel testing. Attention is drawn to the potential usefulness in a screening program of the newly developed clonogenic techniques for growing human tumors. The screening program at the Division of Cancer Treatment is viewed as a dynamic entity, subject to modification in accordance with acquired experience.

A pulse of the protein synthesis inhibitor cycloheximide is shown to induce chromosome aberrations in cultured cells of human origin. These aberrations do not appear until in excess of 12 hr after the pulse and their appearance coincides with the time when cells which had been in S-phase at the time of the cycloheximide pulse reach mitosis. We suggest that the reason why the protein synthesis inhibitor cycloheximide has previously been reported not to induce chromosome aberrations is due to the long delay of cells with damaged chromosomes in reaching mitosis.

Vindesine, a new vinca alkaloid, was administered in thirteen patients with advanced multiple myeloma (stages IIIA and IIIB), resistant to alkylating agents. Eleven patients received two complete courses and could be evaluated. Six patients (55%) showed objective improvement. This was indicated by a decrease of greater than 50% of pretreatment myeloma protein serum levels, normalization of elevated serum calcium levels, and improvement of haemoglobin concentration and renal function. Neutropenia of short duration, mild paraesthesias and alopecia were noted as side effects.

Exposure of the two EBV-negative Burkitt lymphoma lines, BJAB and Ramos, to the abortively cytopathic P3HR-1 substrain of EBV led to an increased expression of C3 receptors within the first twelve weeks. At the twelfth week, 100% of cells carried a high concentration of C3 receptors in both lines. Compared with the receptor pattern of BJAB and Ramos after chronic virus exposure it was seen that after the twelfth week some of the C3 receptors vanished while a certain number of Fc receptors reappeared. These changes in the surface markers are regarded as part of the multiple changes found during exposure to P3HR-1 virus. Apparently, the superinfection initiates a progressive maturation of the cells and the increase of C3 receptors is regarded as an expression of a ‘switch to the right’ in the B-cell differentiation pathway.

A radioimmunoassay was developed with an urokinase antiserum and radioiodinated DFP-inactivated urokinase of 31,000 daltons. Assays of tissue culture medium from ovarian tumours and fetal kidneys showed the presence of urokinase-like immunoreactivity, which could be separated in three molecular forms at gel filtration. All three forms showed inhibition curves parallel to that of purified urokinase. The concentration obtained by the assay corresponded to the enzymatic activity. Distinctly parallel curves were found for tumour cultures of various ages in which the three molecular forms differed in their relative concentrations.