Selective cancer therapeutics最新文献

Temperature sensitive liposomal Adriamycin (LADM) was injected into the hepatic artery of rats bearing implanted hepatic tumors. Two hours after the injection, the liver was heated at 42 degrees C and maintained for six minutes at that temperature using local hyperthermia. Blood samples were taken at regular intervals until 8 hours after injection, at which time the animals were sacrificed and the drug distribution in the tissues was examined. Results indicate that the Adriamycin was released from the liposome, with the drug concentration in circulation peaking at 30 minutes after heating. High drug levels (25.2 micrograms/g of wet tissue) in the tumor and high tumor/liver Adriamycin level ratios (TLAR; 4.1) were found. The drug levels and the TLAR of the liposomal Adriamycin injection combined with heating (LADM H) were significantly different from those of the same dose of aqueous Adriamycin with heating (ADM H) or aqueous Adriamycin (ADM) and LADM without heating. The experiment shows that the LADM is cleared from the liver slowly, and when hyperthermia treatment at phase-transition temperature of the liposome is performed, the drug level in an implanted hepatic tumor is increased, and in the parenchyma is decreased. The results imply that targeting the hepatic tumor in this way may be an effective therapeutic method, and the drug release from the liposome may be controlled externally. This method appears promising for clinical practice.

Adriamycin (Adr) and degradable starch microspheres (DSM) were infused either combined or each separately into the hepatic artery in rats. Liver ATP, GTP, UDP-glucuronic acid, UDP-N-acetyl-hexosamine and energy charge and glutathione were decreased 20 min later with combined treatment but not by Adr or DSM when infused alone. the nucleotide levels were normalized 60 min after the combined treatment. After one week, the Adr rats showed a less weight gain than controls. The Adr + DSM rats lost weight. Only minor changes were found in the livers at microscopical examination at this time.

An assessment was made of 36 extravasations of Adriamycin (doxorubicin) in which vascular access devices had been used. Of these, 25 (69%) were sufficiently severe to warrant removal of the device. Physical manifestations were frequently of delayed onset. Edema and/or erythema often involved extensive areas around the catheter or access device and in several cases were accompanied by pain, discomfort or paresthesia. In 20 patients (59%), spontaneous resolution without ulceration occurred in spite of occasional extravasation of large amounts of doxorubicin. Most extravasations were caused by a limited number of technical errors and equipment problems. These were equally divided by site into injection port extravasations and catheter-related extravasations (18 patients each). The two most frequent causes were needle and catheter tip dislodgements. Procedures are suggested for minimizing the opportunities for extravasation of doxorubicin administered through vascular access devices.

The uptake of cyclophosphamide (CTX) and its metabolites was evaluated by injecting adult female rats with 14C-CTX on the morning of metestrous or proestrus. Rats were sacrificed 1 and 5 hours after 14C-CTX injection. The ovary, uterus, spleen, thymus, liver, kidney, anterior pituitary, duodenum, skeletal muscle and whole blood were isolated from each rat. Samples were combusted using a biological material oxidizer and the resulting CO2 was absorbed and counted. Liver and kidney had the highest uptake of 14C-radioactivity. The ovary appears to have 14C uptake comparable to the thymus and other tissues. Metabolism of CTX by the ovary was investigated by incubating 14C-CTX with human and rat granulosa cells and other ovarian cells obtained from pregnant mares' serum gonadotropin (PMSG)-primed immature rats, in separate experiments. The conversion of CTX to two marker metabolites, 4-ketocyclophosphamide and 4-hydroxycyclophosphamide was negligible and did not change in the presence of luteinizing hormone (LH). It is concluded that 1) following 14C-CTX injection, the ovary takes up a proportion of 14C-radioactivity comparable to other target tissues (e.g. thymus) and 2) the ovary is not capable of activating CTX in vitro in our system.

The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.

The utilization of drug response modulators, based on their physico-chemical properties to augment the cytotoxic response of anticancer drugs is now gaining importance. We present in this communication, investigations performed to assess the antitumor activity of Adriamycin (ADR), on chronic myeloid leukemia (CML) cells, and the effect of bepridil, a calcium channel blocker on the ADR cytotoxicity. Inhibition of 3H-thymidine incorporation into DNA was used as an index of the cytotoxic effects of drugs when utilised alone or in combination. The combination of bepridil (1 and 5 micrograms/ml) and ADR (5 and 10 micrograms/ml) indicated a significant (P less than 0.001) enhancement in the DNA biosynthesis inhibition in CML cells, as compared to those samples exposed to ADR alone. The observed inhibition of DNA biosynthesis was found to be totally reversible, partially reversible and completely irreversible when the CML cells were exposed to bepridil alone, ADR alone and ADR plus bepridil, respectively. Bepridil was found to be highly lipid soluble at physiological pH, and this property could be responsible for the modulation of the ADR activity observed in this study. Results obtained, though preliminary due to the small sample size, clearly indicate a necessity for a detailed evaluation of bepridil effects, which would lead to higher therapeutic gains in anticancer chemotherapy in the clinic.

We have used both HPLC and flow cytometry to measure and compare the uptake of two anthracyclines, menogaril (MEN) and Adriamycin (ADR), in V79 Chinese hamster lung fibroblasts grown as monolayers and as 650 microns multicell spheroids. In order to compare intracellular drug accumulation in spheroid cells measured by the two methods, we converted mean channel fluorescence of the flow cytometer to drug uptake expressed as ng/10(6) cells by using a standard curve. The standard curve related the flow cytometric mean channel fluorescence, of monolayer cells exposed to either drug, to the intracellular drug accumulation determined by HPLC. This standard curve was then used to convert the mean channel fluorescence of cells from drug-exposed spheroids to ng/10(6) cells. Our results show that equal intracellular drug accumulation (determined by HPLC) in spheroids and monolayers does not result in equal cellular fluorescence emission (determined by flow cytometry) by these 2 cell populations. For example, monolayer cells with an intracellular MEN accumulation of 650 ng/10(6) cells, emit 40 units of fluorescence as measured by flow cytometry. However, spheroid cells with the same intracellular accumulation emit about 80 units of fluorescence. This results in the intracellular MEN uptake in spheroids measured by flow cytometry being as much as 2- to 3-fold higher than that measured by HPLC. Intracellular ADR accumulation measured by flow cytometry was also higher than that obtained by HPLC. In spite of the quantitative difference between the two methods, qualitatively both methods gave similar results. Thus, both techniques showed that at equal drug concentration in medium drug uptake in monolayers was much greater than in spheroids.(ABSTRACT TRUNCATED AT 250 WORDS)

In a reproducible murine model of liver metastases, it was demonstrated that liposomal muramyl dipeptide (MDP) as an adjuvant therapy reduces and prevents the development of metastases. C26 colon adenocarcinoma cells were injected into the spleen (5 x 10(4) cells per mouse) of syngeneic BALB/c mice. On day 3, the spleen was removed to prevent a large tumor burden in the spleen. On day 17, 100% of the mice had developed tumor foci in the liver. Liposomal MDP treatment consisted of the i.v. or i.p. administration of 1 mumol of liposomal lipid containing 5 micrograms of MDP per mouse for ten consecutive days. When therapy was initiated two days after tumor cell inoculation, the number of metastases that had developed on day 17 was strongly reduced compared to control mice. Approximately 20% of the mice were free of liver metastases. Initiation of therapy two days prior to tumor cell inoculation enhanced the effect significantly: about 45% of the mice were free of metastases on day 17. The treatment protocol for survival studies was slightly different; liposomal MDP was administered on the first six consecutive days followed by administration twice weekly, through day 24. Control mice died between day 21 and 33 after tumor cell inoculation, whereas liposomal MDP treated mice died between day 26 and 46 with 1 out of 25 mice surviving for more than 120 days. The mortality of the liposomal MDP treated mice that were free of liver metastases was caused by a local tumor at the site of operation.(ABSTRACT TRUNCATED AT 250 WORDS)

The age-related difference of cisplatin (CDDP) pharmacokinetics and ototoxicity were studied in 6 children with solid tumors who received CDDP infusion. CDDP was administered intravenously for 6 hours at a dosage of 30-120 mg/m2 and plasma-free platinum concentrations were determined by atomic absorption spectrophotometry. Plasma-free platinum concentrations ranged from 1.0 to 2.1 micrograms/ml at the end of infusions and declined rapidly with T1/2 of 0.6-1.5 hours. Pharmacokinetic parameters of plasma-free platinum were analyzed in 13 CDDP infusions by the one-compartment open model method. Parameters (Ke, Cl, T1/2 and Vd) of free platinum pharmacokinetics were 0.66 hr-1, 7.71l/hr, 1.35 hr and 15.71l in the younger group (age: 1.7-6.5 years old) and 1.44 hr-1, 11.41l/hr, 0.61 hr and 8.99l in the older group (age: 12.2-15.7 years old), respectively. Up to 600 mg/m2 of the cumulative dosage of CDDP caused minimal ototoxicity in the older group; however, in the younger group, hearing loss at a high frequency zone (6000 and 8000 Hz) began to appear at a cumulative dosage of 200 mg/m2 and progressed to middle zone (3000 Hz) when dosages surpassed 400 mg/m2. These data indicate that the pharmacokinetic difference in age possesses a large distribution volume (Vd) and that slower elimination of the drug in a younger age group is an important factor for age-dependent ototoxicity.