European Journal of Cancer (1965)最新文献

2,3-Dihydro-1H-imidazo [1,2-b] pyrazole (IMPY, NSC-51143) is a new ribonucleotide reductase inhibitor, presently undergoing clinical evaluation, that exhibits prolonged in vivo antitumor activity in experimental animals. Disposition studies were initiated to determine if the prolonged in vivo antitumor activity of IMPY could be explained by its pharmacologic properties. Plasma disappearance curves of radioactivity were biphasic after the i.v. administration of 100, 250 or 500 mg/kg to rats and 250 mg/kg to mice. The distribution phase was rapid in each case ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of approximately 30 min or less), followed by a prolonged elimination phase. Radioactivity was distributed to all tissues of rats and mice including brain after an i.v. dose of 250 mg/kg. In rats, 67.8% of the administered radioactivity was excreted in the urine during the first 24 hr. By 120 hr 74.3% had been excreted via the urine compared with 11.1% in the fees, the latter by biliary excretion. The chromatographic profile of the urine collected from rats and mice 4 hr after drug administration indicated extensive metabolism. Thus, the prolonged plasma and tissue levels of parent IMPY and its metabolites can account for the prolonged duration of cytotoxic activity in vivo.

A phase II evaluation of chlorozoticin (CZT), a water soluble nitrosourea, was undertaken to determine its effectiveness and toxicity in a variety of human metastatic neoplasms. The dosage regimen chosen was either 90 or 120 mg/m² given by i.v. bolus every six weeks. Dosage escalation or de-escalation was dependent on toxicity. There have been 152 patients evaluable for response. The only significant response rates observed were in non-Hodgkin's lymphoma (5/11) and sarcoma (4/27). Single responses were observed in breast and oat cell carcinoma of lung. No responses were observed in melanoma, colorectal, kidney, non-oat cell lung, pancreas, stomach and other carcinomas. Hematological toxicity has been minimal as predicted, but does appear to be cumulative. The major G.I. toxicity has been nausea and vomiting—usually controllable. Occasional hepatic enzyme elevations were observed, and azotemia was observed in 6 patients. Both were reversible. Rare skin and occasional CNS reactions were also seen.

When tested in mice bearing the Ridgway osteosarcoma (ROS) the activity of methotrexate entrapped in small cationic liposomes was increased, both in terms of tumour growth inhibition and toxicity for normal tissues. Conversely, actinomycin D entrapped in small cationic liposomes lost its cytotoxic activity, both against the tumor and normal tissues. In addition, liposome-entrapped actinomycin D proved ineffective therapeutically against a new ROS tumour subline in which resistance to free drug had been derived in vivo; moreover, this resistance appeared to have resulted from failure to retain drug rather than through impaired drug uptake. These results, and those obtained from tissue distribution studies using free and liposome-entrapped actinomycin D, suggested that (a) liposome entrapment modifies the pharmacokinetics and hence activity of these drugs by acting as a slow release system rather than by providing a means of selective delivery to tumours, and (b) the use of liposome-entrapped actinomycin D to overcome drug resistance acquired in vivo may be inappropriate.

Seventy-seven patients with extensive small cell carcinoma of the lung were initially treated with the same combination chemotherapy consisting of cyclophosphamide and doxorubicin. All cases were retrospectively subdivided according to their histological subtype as proposed by the World Health Organization Lung Cancer Classification (WHO): the classic lymphocyte-like (oat cell), type 21, and intermediate cell, type 22. Type 21 has an objective response rate of 43% and type 22 a response rate of 23%. Analysis of the data revealed that the median survival for WHO type 21 was 30.4 weeks; whereas median survival for type 22 was 17.2 weeks (P = 0.04). This difference in subtype response was also seen when response was corrected for Karnofsky initial performance status 40–70 but not for performance status 80–100. Type 21 small cell carcinoma appears to offer a higher response rate to chemotherapy and a longer survival than type 22.

Cell lines from normal or malignant human urothelium, described elsewhere by morphological, cell kinetic and genotypical criteria, have been characterized further by their response to antibody or lymphocyte mediated cytotoxicity in vitro. Four groups of cell lines were included: (1) two fast proliferating cell lines from normal urothelium, (2) three fast proliferating cell lines from transitional cell carcinoma (TCC) together with two transformed sublines of normal derived cell lines, (3) six slowly proliferating TCC lines, and (4) a line from squamous cell carcinoma. HLA antigen expression was demonstrated in the cell lines of groups 1 and 3, but not in lines from group 2 or 4. The sensitivity to spontaneous lymphocyte mediated cytotoxicity (SLMC) of cells in group 1 and 2 exceeded that of cells from group 3 by a factor of 8. The TCC line, HU 456, was more susceptible to SLMC than T 24. Specifically increased cytotoxicity of lymphocytes from patients suffering from interstitial cystitis (IC) against HU 609 from normal urothelium indicated that this line expresses tissue specific antigens, and at the same time that an immune reaction may be part of the pathogenesis of IC. By a sensitive test for antibody-dependent, cell-mediated cytotoxicity (ADCC) antibody activity against HU 456 was found in only one of nine TCC patients and none of five clinical controls. A pronounced non-disease-related blocking serum activity, frequently found, may account for some of the negative findings. The SLMC against HU 456 could be inhibited but not abolished by Fab fragments of rabbit anti-human immunoglobulin, indicating an ADCC mechanism as part of the SLMC.

Accumulating evidence suggests that most common solid tumours in man have latent metastases when clinically detected. Further evidence indicates that when the primary focus is resected, its micrometastases may become enhanced as a result of immunosuppression and other tumour-promoting factors at work in the perioperative period. In this favourable setting, the development of new metastases may also be facilitated from cells forced into the circulation during operative manipulations. It is suggested that the above events are important in the treatment outcome and that they may be prevented to some extent if treatment is first directed to the systemic component of these tumours; resections of the primary focus can be more advantageously done later. Results from experimental and clinical studies as well as many theoretical considerations support the potential value of this approach in the management of operable solid tumours.