摘要:

Membrane receptors for peptide growth factor receptors (PGF-R) play a crucial role In the regulation of cancer cell proliferation and may behave as tumor associated antigens (TAA), which are currently regarded as specific targets for immunodetection and immunotherapy of human cancer. PGF-R are often more expressed by tumor cells than by normal counterparts and, by analogy to TAA, their surface expression may be regulated by cytokines. Moreover, the biological functions and specific ligands of most PGF-R are presently well elucidated as opposed to the great majority of TAA. PGF-R may, therefore, represent ideal cellular targets for at least two different therapeutic approaches: (i) naked or conjugated monoclonal antibodies and (ii) genetically engineered fusion proteins composed of PGF-R physiological ligands linked to genetically modified bacterial toxins. To date, clinical studies based on targeting of receptors for epidermal growth factor and interleukln-2 on tumor cells have been performed. Information from such studies suggests that PGF-R as well as TAA targeting strategies are clinically feasible, but that they still have to be optimized. A variety of host and tumor factors which affect targeting of neoplastic cells have been recently Identified. For instance, it has been demonstrated that the antigenic density of the targeted molecule at the tumor cell surface Is an important factor. In this view upregulation of PGF-R on cancer cells could be of major clinical advantage In Immunotargetlng. It has been reported that several cytokines and chemical compounds can Induce PGF-R modulation on tumor cells. This paper reviews therapeutic opportunities related to the pharmacologic modulation of PGF-R expression. In addition a mechanistic hypothesis regarding PGF-R upregulation induced by cytostatic drugs and cytokines is proposed.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecln which is an Inhibitor of topolaomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicltiea of continuous Infusion (CI) topotecan. This phase I trial first explored a S day CI every 21 day schedule. Doses of topotecan Included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3–4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day Infusion in an effort to ameliorate toxicity and obtain greater dose Intensity (Dl). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 couraes. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3–4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1–2) In the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% Increase In relative dose Intensity). A atesdy-stste plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous Infusion. Minor responses were seen in two patienta with non-small cell lung cancer and three patients with ovarian cancer. In summary, a greater Dl can be achieved with topotecan given on a 3 day schedule than on a 5 day schedule.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We studied the effects of ifosfamide and major motabolites on intracellular glutathlone (GSH) levels in human peripheral blood lymphocytes (PBL). In vitro exposure of PBL to 4-hydroperoxyifostamlde (4-OOH-IF), acrolein or chloroacetaldehyde at 37°C for 60 min led to a concentration dependent depletion of Intracellular QSH. The concentration of the three metabolites to cause a 50% depletion of GSH in PBL was in the micromolar range (acrolein: 16 ± 4 μM; 4-OOH-IF: 22 ± 9 μM; chloroaeetaldehyde: 30 ± 7 μM). Exposure to ifosfamide, the non-activated drug, had no effects on the intracellular GSH levels. Pretreatment with 4-OOH-IF suppressed doee-dependently the lnterleukin-2-lnduced proliferation of PBL. Incubation of PBL together with 2-mereaptoethanesulfonate (mesna) and 4-OOH-IF, acrolein or chloroaeetaldehyde prevented the GSH depletion. The protecting effect of mesna In combination with 4-OOH-IF was independent of GSH biosynthesis, because addition of buthlonine suffoximine had no significant influence on this effect. These findings indicate a novel protective mechanism of mesna against intracellular GSH depletion of PBL during exposure to metabolites of ifosfamide.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Fourteen cancer patients treated with cisplatin received repeated infusions of tropisetron on-demand in conjunction with emesls. In subsequent chemotherapy courses, prophylactic troplsetron was given In a dose Identical to the cumulated dose in study course 1. Troplsetron in study course 1 abolished emesis after 7.5 min (5 mg). Duration of effect was more than 7 h in 50% of the patlents. No relationship between dose and duration of effect was seen. After study course 2, eight of 10 patients preferred prophylactic troplsetron. Two patients with hypertension had a severe Increase in blood pressure probably related to tropisetron. It is concluded that tropisetron has an instant and lasting effect on nausea and vomiting when given on-demand. The majority of patients, however, prefer prophylactic treatment. Hypertension may be a side effect from tropisetron and caution should be displayed in hypertensive patients.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

5-Phenethyl-2'-deoxyurldlne (PEUdR) augmented 5-fluoro-2'-deoxyurldine (FUdR) cytotoxicity up to 100-fold in several human gastric cancar call lines. PEUdR also potantlated 5-fluorouracil (5-FU) cytotoxicity about 5-fold. In contrast, PEUdR reversed 5-fluorourldine (FUR) cytotoxicity in all call lines studied. PEUdR was not cytotoxic up to 200 μM. PEUdR inhibitad tha incorporation of and [14C]uridine into acld-inaolubla free-tiona, and also inhibited uptaka of [3H]thymldlna into KATO III cells. Thus, PEUdR inhibits pyrimidine nucleo-side transport and salvage enzymes, which potentiates the cytotoxicity of FUdR and reverses tha effect of FUR in human gastric cancer cells. These results may contribute to mora effective cancer chemotherapy with FUdR and 5-FU.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The antimetastatic activities of synthetic peptides corresponding to fragments of the adhesion-related molecules, such as flbronectin and laminin, were examined. We prepared three peptides derived from the type III connecting segment domain (IIICS) of flbronectin: Glullo-Leu-Asp-Val (EILDV), Qlu-lle-Leu-Aap-Val-Pro-Ser-Thr (EILDVPST), Arg-Qlu-Aap-Val (REDV), and a lamlnln-re-lated peptide, Tyr-lle-Gly-Ser-Arg (YIGSR). Each peptide inhibited the experimental tumor metastasis of B16-BL6 melanoma, while EILDV had the strongest effect. The peptides conjugated with poly(ethylene glycol) (PEG) were more effective than the unmodified peptides in molar ratio terms. A mixture composed of PEG hybrids with EILDV, REDV and YIGSR significantly Inhibited tumor metastasis.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Compound 4d ((E)- and (Z)-1,1-Dlchloro-2-[4-(benzyloxy)-phonyl]2,3-ble(4-methoxyphenyl) cyclopropane) and compound 5c ((2>1,1-Dlchloro-2-[4-(bonzyloxy)-phenyl]-2-(4-mothoxyphenyl)-3-phenylcyclopropane) are two members of a novel series of triarylcyclopropyl compounds which have been shown to be pure antiestro-gana. In the present study, the antiproliferative activity of 4d and 5c was examined on estrogen receptor (ER)-posltlve MCF-7 and ER-negatlva MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells. Compound 4d Inhibited the growth of MCF-7 cells In a dose-related manner over a concentration range of 10−13to 10∼6 M while compound 5c Inhibited MCF-7 cell growth in a dose-related manner over a concentration range of 10−13to 10−5M. Further, neither compound altered the growth of MDA-MB-231 or A-549 cells. Co-adminiatratlon of estradiol reversed the antiproliferative activity of 4d but not 5c on MCF-7 cells. Both compounds bound specifically to ER in MCF-7 cells; however, the relative binding activity of 4d was five times greater than estradiol and 5000 times greater than 5c. The influence of 4d and 5c on the cell surface morphology of MCF-7 and MDA-MB-231 cells was studied using scanning electron microacopy. Both compounds, at a concentration of 10−6M, reduced the density of microvilli on MCF-7 cells, which was reversed by co-admlnlatration of estradiol (10−8M). These compounds did not altar the cell surface morphology of ER-negatlve MDA-MB-231 cells. In conclusion, the results of this study indicate that compound 4d la mora potent than 5c as an Inhibitor of breast cancer cell proliferation and suggest that a polar methoxy group on the ± phenyl ring of compound 4d contributes to ER binding and ER-medlated antitumor activity. Further, these results suggeet that one or both of these compounds may be highly effective in the treatment of estrogen-dependent breast cancer.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The possibility of Inhibiting gone axprssslon with anti-IWM ollgonuclsotldss (A3 ODNs) In combination with mora conventional chemotherapy is a vary attractive modality in oncology. Howavar, possible Interaction between the ODN and drug must be considered. Here wa show that ODNs protect cells from the cytostatic/cytotoxic action of actinomycin D (AMD), adriamycin, dauno-mycln or qulnacrlne, but not mitomycin, camptothecin, vincristine, clsplatin, etoposide (VP-16) or cyclohoximida. The cytoprotectlve effect depends on ODN length as well as ability to Interact directly with the cytotoxic drug and Is only slightly sequence selective.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Photodynamic therapy (PDT) is systemic administration of tumor localizing photosensitizers and subsequent Irradiation with light of the appropriate wavelength. The combination of drug uptake in malignant tissues and selective delivery of laser-generated light provldea effective therapy, with efficient tumor cytotoxicity and minimal normal tissue damage. There have been few studies of the effects of photoactlvated photosensitlzers on the host Immune response. Since immunity is Important in the control of tumor growth and spread, we have examined, in our laboratory, the effects of photoactlvated phthalocyanlnea on the antitumor immune response. Immunosuppressed and normal mice bearing the MS-2 fibrosarcoma trested with 5 mg/kg of aluminum dlsulfo-natad phthalocyanine (AlS2Pc) and then the tumor mass exposed to laser light (100 mW/cm2x 10 min) or treated with surgical excision of the tumor survived Indefinitely, with no difference between the different groups. The survivors, tumor-free 100 daya after the treatment modalities described above, were rechallenged with the parental MS-2. Some groups of surviving animals were Immunosuppressed with cyclophosphamide before the Injection of the tumor. Roslatanco to rechallenge waa evidenced only In normal surviving animals cured by PDT, while the immunodepressed surviving animals and animals cured by surgery died of tumor. Finally, mice, cured by PDT and tumor-free, rechallenged with L1210 and P388 murine leukemias did not survive. These results suggest that a potential and specific 'antitumor Immunity' is induced by PDT with photoactivated AlS2Pc.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A toxicology study of DENSPM was carried out In rats by multiple (once dally for 5 days) Intravenous Injection. Doses of 12.5, 25 and 50 mg DENSPM/kg were well tolerated. Infusion of 100 mg DENSPM resulted In distressing physical signs, Including labored breathing, convulsivs movements and acute death. There were no end-organ toxicities induced by this regimen as evaluated by serum chemistry and hematology examinations, and histopathologic exam of all major body organs. Transient hypotension was Induced In rats and dogs by rapid infusion of DENSPM; ths magnitude of this hypotension was decreased by slow infusion of DENSPM Into dogs. Hypotension appears to be the dose-llmlting toxicity of this agent when Infused rapidly.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID