Selective cancer therapeutics最新文献

Tumor growth was studied in a peritoneal tumor model in the rat after intravenous and intraperitoneal administration of doxorubicin (4 mg/kg), mitoxantrone (2.5 mg/kg) and cisplatin (4 mg/kg) and after intraperitoneal administration of carboplatin (20 mg/kg). All treatments delayed tumor growth and intraperitoneal treatment was more effective initially than intravenous treatment for all drugs tested. Regrowth occurred between 2 and 7 weeks after treatment and was less pronounced after intravenous treatment. Tumor sizes in cisplatin treated rats 7 weeks after treatment were comparable after intraperitoneal and intravenous treatments. Intraperitoneal carboplatin even with a dose 5 times higher than cisplatin resulted in a less tumor growth delay in all stages of the treatment, compared to cisplatin. All cytostatic drugs, except carboplatin, induced loss of body weight. Weight loss was similar for intraperitoneal and intravenous treatment with both cisplatin and mitoxantrone while for doxorubicin the weight loss was significantly higher after intravenous treatment than after intraperitoneal therapy. Considering the "therapeutic index", defined as the ratio of tumor growth delay to weight loss, cisplatin had the highest "therapeutic index", 1.5 (intraperitoneal) and 1.7 (intravenous) compared to 0.3 (intraperitoneal) and 0.6 (intravenous) for Mitoxantrone and 0.4 (intraperitoneal) and 0.5 (intravenous) for doxorubicin. This indicated that cisplatin was the most favorable drug to use in this peritoneal tumor model for both intraperitoneal and intravenous treatment. The tumor growth delay was initially more pronounced after intraperitoneal cisplatin compared with intravenous.

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurements of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chest and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on a weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.

Rats with solitary liver tumors were treated with adriamycin administered via the hepatic artery with and without degradable starch microspheres. Tumor growth inhibition was significantly greater, and tumors were decreased in size 7 days after, following treatment with adriamycin + microspheres. The bone marrow seemed to be protected. However, the addition of microspheres to adriamycin gave a body weight loss and evidence of increased liver damage. Possible interrelations between liver damage, antitumor effect and body weight loss are indicated.

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.

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)

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.