Selective cancer therapeutics最新文献

Fifteen patients with progressive primary malignant or metastatic brain tumors were treated on a clinical and pharmacokinetic study with intracarotid cisplatin and bleomycin. Toxicity was tolerable and consisted mainly of nausea and vomiting. Neurologic toxicity included focal seizures (1), leukoencephalopathy (1), and motor weakness (1). Five patients had improvement in CT scans and four patients had stabilization of disease. Recommended dosage for future clinical trials are cisplatin 60 mg/m2 and bleomycin 100 units. Pharmacokinetics of intracarotid cisplatin revealed the jugular vein concentration was twice the peripheral vein level at the end of infusion. Cisplatin is a drug which has demonstrated in vitro activity against malignant gliomas (1). Clinical trials with intravenous administration of cisplatin has shown definite, although limited antitumor activity against primary brain tumors (2,3,4) and metastatic brain tumors (5,6). To enhance its antitumor effect, cisplatin has been administered by the intracarotid route (7,8,9). The results appear encouraging, but neurological and ophthalmological toxicity may occur (8). In our initial study with intracarotid cisplatin, 35 patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy were treated. Of 20 evaluable patients with primary tumors, 6 responded to therapy and 5 had stable disease. Five of 10 evaluable patients with brain metastases responded and 2 had stable disease. For responding primary brain tumor patients the median time to progression was 33 weeks. The recommended dose for intracarotid cisplatin was 60-75 mg/m2 administered every 3-4 weeks (7,8). Higher cisplatin doses produced more central neurological toxicity. There is limited data on the central nervous system pharmacology of cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined whether vinblastine (VLB) encapsulated within multilamellar vesicle-liposomes (MLV) would reverse target cell resistance to the drug exhibited by the UV-2237M murine fibrosarcoma and its Adriamycin (ADR)-selected multidrug resistant (MDR) variants. Resistant fibrosarcoma cells were grown in medium containing 1 and 10 micrograms/ml ADR to yield the MDR lines UV-2237M/ADRR (ADR-1) and UV-2237M/ADRRR (ADR-10), respectively. VLB encapsulated in MLV composed of phosphatidylcholine (PC) and phosphatidylserine (PS) (7:3 molar ratio) was hydrophobic, occupied an internal space equivalent of 6.13 microliters/mumol, and was stable in medium at 37 degrees C for up to 6 days. The 50% inhibitory concentrations (IC50) of VLB were 2, 25, and 70 ng/ml for the parent, ADR-1, and ADR-10 cell lines, respectively. VLB in MLV significantly enhanced sensitivity of tumor cells to VLB. The respective IC50 of liposomal VLB were 0.5, 5.7, and 12 ng/ml for the parent, ADR-1, and ADR-10 lines. MLV containing saline were not toxic to the cells. These data indicate that presentation of VLB entrapped in PC:PS MLV provides a method to overcome tumor cell resistance to this drug.

The effect of calcium antagonist verapamil on the uptake and efflux of Etoposide (VP16), a semi-synthetic derivative of podophylotoxin and a broad spectrum antineoplastic agent, has been investigated and compared in sensitive (UM-UC-2) and resistant (UM-UC-9) human bladder cancer cells, and L1210 leukemia cells, by using both radioisotope (3[H]-VP16) liquid scintillation and high performance liquid chromatography assay with electrochemical detection. The uptake of VP16 was rapid in all three cell lines, showing an initial rapid linear phase followed by a second slower phase, but at steady state the ratios of intracellular to extracellular VP16 concentrations were only 0.004-0.006. No significant difference in drug uptake was observed in sensitive UM-UC-2 and resistant UM-UC-9 cells at all concentrations studied. Verapamil at a concentration of 10 microM enhanced the intracellular VP-16 levels in all sensitive and resistant cell lines. The increments were 21.5% for UM-UC-2, 11.8% for UM-UC-9, and 31.0% for L1210 cells after 30 minutes incubation with 1 microM VP16. A slower efflux of VP16 was observed in verapamil treated cells in all three cell lines. There was a small increase in the nonexchangeable components in verapamil treated cells, although only 5-10% of VP16 was retained. No peak other than that of VP16 was detected in the HPLC chromatogram of extracts from both cell pellet and influx or efflux medium.

Doxorubicin (DOX) is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Pentoxifylline (PTX) is a non-toxic methylxanthine used clinically for the treatment of intermittent claudication. It is an active haemorheological agent, used for the treatment of defective microcirculation. In the present study, we employed PTX as a drug response modulator in combination with DOX to achieve increased cytotoxicity in human chronic myeloid leukemia (CML) cells. Inhibition of 3H-TdR incorporation was used as a measure of cytotoxicity. PTX at 100 microM concentration significantly (P less than 0.001) potentiated DOX-mediated DNA biosynthesis inhibition in CML cells in vitro. Significant synergistic inhibition was seen in 13 out of 22 CML samples. Decreased DOX accumulation is a characteristic feature of DOX resistant tumor cell lines. Drug accumulation studies demonstrated that PTX significantly (P less than 0.02) increased the intracellular accumulation of DOX in the CML cells. The enhanced DOX accumulation can be a mechanism of increased cytotoxicity by DOX-PTX combination.

Colony formation assay systems are an important part of in vitro drug evaluation. It would be useful if the in vitro drug cytotoxicity could be carried out under conditions mimicking those employed clinically. We have developed an individual colony formation assay system that would allow monitoring and quantitation of the growth of individual colonies (9) in the presence of the drug under conditions of continuous and/or short-term exposure, after plating of the cells in the agarose. In this brief report, we established the pharmacokinetic profile of four drugs, cytosine arabinoside (araC), Doxorubicin (Dox), 5-fluorouracil (5-FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) in agarose mimicking those that are achieved when these agents were administered in vivo as an i.v. push. The results show that short-term treatment in agarose is possible and that the washing procedure of the drugs decreased the drug concentrations 3-4 logs over 44 hours.

In previous studies we found degradable starch microspheres (DSM) to increase the antitumor effect of adriamycin injected by the hepatic artery in rats with a liver adenocarcinoma. Increased side effects also appeared, namely body weight loss and liver necroses. In the present paper, norepinephrine in four different protocols was added to the injection of adriamycin + DSM to decrease the drug flow to normal tissues. In two protocols norepinephrine decreased the body weight loss. There was also a non-significant decrease in liver necroses but also in antitumor effect. In these experiments we also observed that some rats given adriamycin + DSM got gastric necroses. This was not found when norepinephrine was added. Addition of propranolol to norepinephrine did not decrease side effects. Vasoactive drugs may therefore be of value to diminish adverse side effects of the combination cytostatic agent + DSM, probably decreasing overspill into normal tissues.

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.