摘要:

Flavone acetic acid ester (NSC 293015, LM 985) emerged from a series of flavonoids from Lyonnaise Industrielle Pharmaceutique (Lipha) screened by the National Cancer Institute. LM 985 showed modest but sufficient activity in the P388 pre-screen to progress to secondary evaluation on the solid colon 38, where significant activity was seen. On the basis of this particular profile LM 985 was selected by the Cancer Research Campaign (CRC) UK for phase I clinical trial. It was not recommended for phase II trial because of drug associated hypotension and the fact that it appeared to act as a pro-drug for flavone acetic acid (NSC 347512, LM 975, FAA) which was shown to be responsible for the dramatic solid tumor activity in mice. This was manifested as dramatic hemorrhagic necrosis and involves a complex mechanism of action. FAA proceeded to clinical trial but unfortunately no anti-tumor activity was seen. A large amount of effort has been channelled into identifying the mechanisms of action of FAA in mice and it is clear that activity relies on a number of factors. Subcutaneous tumors respond dramatically whereas ascites tumors and tumor deposits in other sites are usually less responsive. Establishment of a tumor blood vasculature system appears necessary for response and adequate drug concentrations within a therapeutic window are necessary. From the large body of information available at present the most likely explanation for discrepancies in activity between mouse and man seems to relate to differences in the ability of the immune system to respond to FAA, although variation in the composition of the vasculature cannot yet be ruled out. Analogs of this type of compound are worth pursuing but it is necessary to examine them in appropriate model systems in order to predict for possible clinical activity.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Combretastatin A-4 is a natural product which was isolated from the South African treeCombretum caffrum. In this study, the cytotoxic activity of combretastatin A-4 was tested in radiometric and human tumor cloning assays against eight different tumor cell lines and against 15 patient tumors in the human tumor cloning assay. To test the preferential cytotoxicity of combretastatin A-4 against tumor cells versus non-tumor cells, it was also tested in the radiometric assay against both normal human diploid fibroblasts and human bone marrow cells. Of the eight cell lines used, combretastatin A-4 showed preferential cytotoxicity for six of them. In addition, combretastatin A-4 showed a concentration-dependent cytotoxicity against a variety of human tumors. Based on the data generated in this study, combretastatin A-4 should be further tested inin vivopreclinical models.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Rats received an intraperitoneal bolus injection of etoposide at 5 mg/kg of body weight in the form of an etoposide microcrystal suspension in oil (ETOP-OIL) or an aqueous etoposide solution. The tissue distribution was subsequently analyzed using high performance liquid chromatography. ETOP-OIL delivered significantly greater amounts of etoposide and for a longer duration to the intraperitoneal tissues such as the omentum and the spleen, whereas it delivered significantly less etoposide to the rest of the body such as the lung, the heart and the bone marrow, than the aqueous etoposide solution.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The combination of interferon (IFN)-α2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-α2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Hydroxyrubicin, a synthetic doxorubicin analog in which the basic amino group at C-3' is replaced by a hydroxyl group, was used as a prototype compound to study the effects of basicity of the sugar moiety on the toxicity and antitumor activity of anthracycline antibiotics. Compared with doxorubicin, hydroxyrubicin showed similar or superiorin vitrocytotoxicity against P388, L1210, and M5076 cells, as determined by an MTT assay, and against 8226 and CEM cells, as determined by a growth inhibition assay. Hydroxyrubicin was 5 and 13 times more effective than doxorubicin in inhibiting the growth of multidrugresistant CEM (CEMvbl) and 8226 (8226R) cells, respectively. Hydroxyrubicin was not cross-resistant with doxorubicin in a cytotoxicity assay against KB 3-1 and KB V1 cells (resistance index 1.1 for hydroxyrubicin versus > 15.6 for doxorubicin). Cellular uptake and retention of hydroxyrubicin were studied by flow cytometry in parent and multidrug-resistant 8226 cells, and compared with those of doxorubicin. In 8226 sensitive cells, 2 h uptake and retention of doxorubicin were similar or higher than those of hydroxyrubicin. In 8226R cells, uptake and retention of hydroxyrubicin were about 3-fold higher than those of doxorubicin. In mice, the acute LD50of hydroxyrubicin was about 3-fold higher than that of doxorubicin (79.1 versus 25.7 mg/kg). At equitoxic doses, hydroxyrubicin was as myelosuppressive as doxorubicin but less cardiotoxic, as assessed by the Bertazzoli test. In contrast to doxorubicin, hydroxyrubicin, due to the lack of basic amine function, showed no selective interaction with negatively-charged cardiolipin (CL). The observed decrease of affinity to CL might be responsible for the reduced cardiotoxicity of hydroxyrubicin. Inin vivoantitumor activity studies, hydroxyrubicin at the optimal dose (37.5 mg/kg, i.p., on day 1) had significant activity against intraperitoneal P388 leukemia resistant to doxorubicin, whereas doxorubicin (10 mg/kg, i.p., on day 1) was inactive (%T/C 1637ndash;200 versus 118–120). These studies indicate that: (i) the amino group at position 3' is not essential for doxorubicin to exert its biological activity, (ii) removal of the basic center (deamination at the C-3') results in an increased cellular uptake and retention, (iii) the increased cellular uptake and retention of hydroxyrubicin in multidrug-resistant cells correlate with a partial or total lack of cross-resistance of this analog with the parent compound, doxorubicin, and (iv) deamination at position 3' confers a reduced cardiotoxicity and diminished affinity for CL.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2intravenously over one hour, on a daily × 5 schedule every 3 weeks. Toxicities of grade 3 or above Included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0–9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A phase I trial with continuous intravenous infusion of lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutaneplatinum (ll)-lactate) for 72 h was performed to determine the maximum tolerated dose (MTD). Each patient received a single dose level, the total dose of lobaplatin ranged from 30 to 60 mg/m2/72 h every 4 weeks. Eleven patients enroled in this study and received a total of 30 courses of lobaplatin (median 2; range 1–6). Thrombocytopenia was the dose-limiting toxicity, it reached WHO grade III in three out of six patients at 45 mg/m2/72 h, and WHO grade IV in two out of two patients at 60 mg/m2/72 h. Leucocytopenia was mild, as was nausea and vomiting. Phlebitis at the infusion site was found in three patients. During this trial there were no signs of renal, neuro- or ototoxicity. One patient with ovarian cancer, pretreated with three different platinum complexes, achieved a partial response now lasting for longer than 6 months. In conclusion, thrombocytopenia is the dose-limiting toxicity of lobaplatin administered by 72 h continuous infusion. The recommended phase II dose for this regimen is 45 mg/m2/72 h every 4 weeks.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We investigated the liposome forming properties of three homologues of alkylphosphocholines: hexadecylphosphocholine (HPC), octadecylphosphocholine (OPC) and eicosanylphosphocholine (EPC). In the presence of cholesterol and dicetylphosphate, alkylphosphocholines form liposomes with slow permeability for entrapped carboxyfluorescein. We studied the direct cytotoxicity of alkylphosphocholine vesicles and their ability to attack MethA sarcoma cells, human skin and muscle fibroblasts (M22, GUS, Moscow), and human mouth epidermoid carcinoma cells (KB, ATCC, CCL 17). All alkylphosphocholines show cytotoxic activity against the investigated cells, the degree of which depends on the number of carbon atoms in the alkyl chain, concentration and incubation time. Whereas the etherlipid liposomes are less toxic to MethA cells than the free compounds, the liposomal alkylphosphocholines are more toxic toward KB and M22 cells than the corresponding free lipids.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The cytolyticClostridium perfringensdelta toxin lyses selectively cells which express ganglioside GM2. In this study, we investigated whether delta toxin can be used to characterize GM2 on tumor cell membranes and as an antitumor agent. The sensitivity to lysis by delta toxin of various murine and human malignant cell lines and also normal tissues was quantified using a51Cr-release assay. The cytotoxicity titers were correlated with the125I-labeled toxin binding capacity of sensitive and insensitive cells. Seven of eight human melanomas tested were lysed by the toxin and, of these, four were very sensitive (cytotoxicity titers below 12 ng of toxin). All neuroblastomas, gliomas and the retinoblastoma tested were lysed with 3–18 ng of toxin. Three of six carcinomas and one of two sarcomas were also very sensitive (cytotoxicity titers 0.6–15 ng) whereas leukemias and lymphoma cells were insensitive. Normal human tissues were insensitive (erythrocytes, skin fibroblasts) or poorly sensitive (brain, lung, spleen). Thein vivoantitumor activity of delta toxin was tested in tumor-bearing mice. Daily intra-tumor injections of 0.5–1 mg of toxin for 4–5 days in carcinoma Me180- and melanoma A375-bearing nude mice, and neuroblastoma C1300-bearing A/J mice significantly inhibited tumor growth for 12–36 days. Intravenous administration of 100 ng of toxin per day for 5 days in Me180- bearing nude mice and C1300-bearing A/J mice gave significant inhibition of tumor growth only during the treatment period, and 10 injections of the same dose of toxin had no significant effect on SK-MEL28, a tumor lacking GM2.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We constructed a recombinant plasmid, pBHIV1, carrying the long terminal repeat (LTR) sequences of HIV-1 linked to the reporter chloramphenicol acetyl transferase (CAT) gene and to the aminoglycoside phosphotransferase (aph) gene as a selectable marker. We have introduced pBHIV1 in a human ovarian cancer cell line A2780 and in a cisplatin resistant variant 2780CP, and obtained stable geneticin resistant A27HIV1-1 and 27CPHIV1-1 cells, respectively. Both transfectant cells express CAT activity from the HIV LTR promoter. The response to the anti-neoplastic drug cisplatin was studied on the LTR regulated CAT activity in both cell lines. It was found that cisplatin at 2.5 × 10−5M concentration stimulates the expression of CAT by 26-fold from the HIV LTR in A27HIV1-1, but requires a concentration of 5 × 10−5M to enhance expression by 4.1-fold in the cisplatin resistant 27CPHIV1-1 cells. Carboplatin, over a range of concentrations (1 × 10−6to 1 × 10−4M), does not stimulate expression of CAT from the HIV-1 LTR in either of the transfected cells.

ISSN:0959-4973    

出版商:OVID    

年代:1993

数据来源: OVID