摘要:

The discovery of hypothalamic hormones, especially LH-RH and somatostatin has id to practical clinical uae of their analogs In tha field of cancer traatment. Bombesin/GRP antagonlsts can ba also consldarad for the development of new methods for treatment of various tumors. The undarstandlng of functions of these peptide hormones and the availability of their synthetic analogs should permlt the ciiniclans to treat a variety of cancers more successfully than in the past.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Prostaglandins (PGs) with antiproliferative activity against tumor cells consist of the cyclopentenone PGs and the alkylidene cyclopentenone PGs. Such PGs are PGD2, PGJ2, δ12-PGJ2, PGAL δ7-PGA1and PGA2. Both PGJ2and δ12-PGJ2are ultimate metabolites of PGD2and have potent antiproliferative activity on tumor cells. δ12-PGJ2was identified in human urine, whereas δ7-PGA1has not been found In the human body. One Important characteristic of both δ7-PGA1and δ12-PGJ2Is that they have little cross resistance with clsplatin and adriamycinIn vitroandIn vivo, δ7-PGA, has 5-fold greater antitumor activity than δ12-PGJ2. Methyl ester-δ7PGA1(methyl-δ7-PGA1) Is stable chemically and can be easily synthesized In large amounts. All four Isomers of methyl-δ7-PGA1showed the same antiproliferative activities on ovarian carcinoma cells. In addition, methyl-δ7-PGA1integrated in lipid microspheres (llpo-methyl-δ7-PGA1) Is more soluble In water than methyl-δ7-PGA1alone. Hence, lipo-methyl-δ7-PGA1was selected for extensive preclinical studies. Intravenous administration of lipo-methyl-δ7-PGA1could Inhibit the growth of both HeLa S3 and Lovo colon cancer cells transplanted subcutaneously In nude mice. Lipo-methyl-δ7-PGA1by intraperitoneal administration could prolong the survival of scid mice bearing 2008C/13*cells resistant to cisplatin. The combined administration of cisplatin and lipo-methyl-δ7-PGA1prolonged the survival of nude mice bearing HRA cells compared with each single agent alone. Consequently, phase 1 clinical studies of lipo-methyl-δ7-PGA1In refractory ovarian cancer and colon cancer are planned. δ7-PGA1demonstrates irreversible binding to thiois, whereas PGA1shows reversible binding. Both δ7-PGA1and lipo-methyl-δ7-PGA1are metabolized to unknown products in human serum, whereas the latter is converted to δ7-PGA1in rat serum. The half-life of δ7-PGA1was 1.5 h in human serum, whereas that of methyl-δ7-PGA1was 13 min. The half-life of lipo-methyl-δ7-PGA1was almost the same as that of methyl-δ7-PGA1. On the other hand, δ12-PGJ2was stable in human serum. Lipo-methyl-δ7-PGA1showed less toxicity than δ7-PGA1and δ12-PGJ2. LD10and LD50for single administration were 17.4 and 33.5 mg/kg for male rats, and 38.1 and 45.9 mg/kg for female rats, respectively. All rats tolerated repeated administration of 10 mg/kg/day lipo-methyl-δ7-PGA1for 28 days. However, loss of weight was observed after 14 days of administration. Slight anemia was recognized with decrease of both red blood cell count and hemoglobin. However, the dose-limiting factors remain undetermined. The inhibition of DNA synthesis by antitumor PGs Is Independent of AMP. PGs were transferred into the nucleus, and δ12-PGJ2covalently bound to nuclear proteins and inhibited RNA synthesis. With respect to their antiproliferative activity, the primary effect of PGA1, PGD2, δ7-PGA1and δ12-PGJ2was to block cell progression from G1to S in the cell cycle. Both PGA1and PGJ2Induced the synthesis of a 70 kDa protein (p70) which was Identified as a heat shock protein related to the major 70 kDa heat shock protein group. The G1block is associated with both inhibition ofmycgene family expression and Induction of heat shock proteins. High dose administration of either PGA2or δ12-PGJ2resulted in significant G2/M arrest and apoptosis. The PGs with a cyclopentenone ring have antiviral activity. PGJ2is a potent antiviral agent against Sendal virus and herpes simplex virus. In addition, PGA1and 16,16-di-methyl-PGA2-methylester suppressed the proliferation of HIV-1-Infected cord blood lymphocytesIn vitro. The potency of antiviral activity was δ7-PGA1> PGA1> PGA2. The cyclopentenone ring seems to have a universal action of both antitumor activity and antiviral DNA activity.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Photodynamic therapy of cancer is based on the photosensitizing ability of dyes which, after administration, are present in a somewhat higher concentration in tumors than in surrounding normal tissue. After light activation of the sensitizer, singlet oxygen and probably oxygen free radicals are formed and consequently all kinds of cellular components are affected. This review focuses on cellular and biochemical aspects of photodynamic therapy. Both damage to different cellular targets and cellular responses after photodynamic treatment are discussed.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Didemnin B Is a cyclic peptide Isolated from the marine tunicateTrididemnin cyanophorum. It is a known potent Inhibitor of RNA, DNA and protein synthesis, with activity against the murine B16 melanoma. Fourteen patients with disseminated malignant melanoma were evaluated in a Southwest Oncology Group phase II trial of didemnin B at 4.2 mg/m2by 30 min i.v. infusion every 28 days (SWOG-8754). Only patients with no prior chemotherapy were eligible; prior radiation therapy, surgery and at most one prior biologic regimen were allowed. Patients with brain metastasis were eligible only if the disease in the brain had been treated and controlled. All patients had to have normal renal and hepatic function and adequate granulocyte and platelet counts, a performance status of 0–2, and bidimensionally measurable disease. Fourteen patients were entered on the study; five received one and nine received two courses of didemnin B. No responses were noted among the 11 patients evaluable for response. Five patients developed unusual but reversible hypersensitivity reactions during the second course of therapy. Other toxicity in this trial was nausea and vomiting and diarrhea, none of severity greater than grade 3. Given the lack of antitumor efficacy and the unusual toxicity, further evaluation of didemnin B in this dose and schedule in malignant melanoma is not warranted.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Sulofenur (LY186641), a diaryisulfonylurea, was evaluated clinically utilizing either a dally × 21 schedule or a dally × 5 (with 2 days off) for 3 weeks schedule. Eighteen patients with refractory solid tumors received 47 evaluable courses of sulofenur given p.o. dally × 21 every 28 days at five dose levels while 14 received 29 courses of sulofenur given daily × 5 for 3 weeks every 28 days at three dose levels. Toxicities Included anemia, methemoglobinemia and hemolysis. One patient experienced a fatal subendocardial Infarction on the dally × 21 schedule. One partial response was observed in a patient with a sertoll cell tumor on the dally × 5 for 3 weeks schedule. Dally × 5 for 3 weeks Is the schedule recommended for phase II trials.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

An original method is proposed for the purpose of discriminating between antimetabolites exhibiting different operating mechanisms. The present work was carried out by means of the digital cell Image analysis of Feulgenstained nuclei cultured In the presence of different antimetabolites. We chose this method because it enables anticancer drug-induced effects to be studied at both morphonuclear and cell cycle levels in the same biological sample. The results show that all the antimetabolites had similar effects on the nuclear texture of the cells and on cell cycle parameters. Furthermore, the use of multivariate analyses made it possible to distinguish between different mechanisms of action among drugs belonging to the same class of antineoplastic, I.e. anti-metabolite agents.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The use of viability assays to assess the effect of antineoplastic agents on cell lines and tumor cells is an important Investigative tool and may have clinical relevance. Such assays require very small quantities of drugs and it is the practice of many laboratories to freeze aliquots of drugs for use in these assays as required. We have investigated the stability of 11 different agents in an ATP-based chemosensitivity assay which is being evaluated for clinical use. The results show that most drugs maintain their biological activity well when frozen at −20°C for periods up to 24 months, or occasionally at room temperature. However, 4-hydroperoxycyclopho-sphamide and mitomycin C are exceptions to this rule, and should not be kept frozen for more than 2–3 months. Cisplatin is unstable when frozen and then thawed, but maintained activity at room temperature for at least 6 months. Since biological activity may not correlate completely with chemical stability, further studies on the effect of storage are required, but it seems unlikely that the appropriate use of frozen aliquots is a major source of error in tumor chemosensitivity assays.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Cytochemical and autoradiographic studies in Wistar rats [Crl:(WI)BR] show that cisplatin treatment (9 mg/kg) Inhibits the release of acetylcholine from the axonal endings of the stomach smooth muscle resulting in bloating of the stomach and ulceration. Cisplatin also induces corticosteroid release from the adrenal gland stimulating peptic ulceration. Vagotomy helps ameliorate the effect but not eliminate it. Calcium supplementation restores normal neuromuscular function to gastric smooth muscle, thereby eliminating the gastro-intestinal toxicity due to cisplatin.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A new dosage formulation (MTX-CH) comprising methotrexate (MTX) adsorbed onto a suspension of activated carbon particles was developed for the treatment of lymph node metastases.In vitrostudies showed that activated carbon particles adsorbed a great amount of MTX. Subcutaneous Injection of MTX-CH Into the left hind foot pad of rats distributed a greater amount of MTX selectively to the regional lymph nodes (the left popliteal node and the para-aortic nodes) for a longer period of time than similar administration of MTX aqueous solution with a smaller amount of MTX distributed to the rest of the whole body.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We have compared the cellular uptake and subcellular localization of14C-labeled bieomycin-A2(BLM) and de-glycobieomycin-A2in living KB3cells. Both drugs exhibit poor internalization into cells but reveal significantly different Intracellular distribution, with low and high accumulation into the cell nuclei for BLM and deglyco-BLM, respectively. The results indicate that the carbohydrate chain does not constitute a limiting factor for BLM permeation and is directly implicated in the Intracellular distribution of the drug into cells.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID