Selective cancer therapeutics最新文献

Young adult male and female beagle dogs were infused with single doses of 0.5 (2 dogs) or 0.25 mg (5 dogs) Mitomycin C (MMC)/kg body weight directly into the internal carotid artery. Serial hematology and serum chemistry profiles, electrocardiograms and physical observations were made, the animals necropsied at varying times after dosage, and the major organs examined histologically. Results indicate that the dose limiting toxicity of this treatment regimen is myelosuppression. No ocular or neurologic toxicity was detected in any test animal. The findings suggest that infusion of MMC can be safely attempted in humans for the treatment of brain tumors that derive their blood supply from the internal carotid artery.

Free doxorubicin and doxorubicin associated with polyisohexlycyanoacrylate were tested for their therapeutic efficiency in hepatic metastasis-bearing mice. The metastases originated from the M 5076 reticulum cell sarcoma. Irrespective of the dose and the administration schedule, the reduction of the number of metastases was much larger with the doxorubicin-loaded nanoparticles than with free doxorubicin. This was clearly confirmed by histological examination. Although pharmacological and pharmacokinetic data indicated a strong capture of the nanoparticles by the hepatic issue, the mechanism of nanoparticle therapeutic efficiency remains unclear.

The blood-brain barrier presents a major obstacle to the systemic treatment of malignant brain tumors and brain metastases. We investigated whether the direct injection of liposomes into the internal carotid artery of normal mice or mice with experimental brain-melanoma metastases could allow delivery of anticancer drugs across this barrier. Liposomes of different sizes (greater than 5 microns, less than 1 micron, 40-80 nm) and lipid compositions were injected i.v. or into the internal carotid artery. The retention of liposomes in the brain of normal C3H/HeN mice was similar to that observed in mice with experimental brain cancer metastasis. The highest accumulation of liposomes in the brain occurred with large multilamellar vesicles, which also produced severe toxicity presumably due to embolism. Smaller liposomes were not toxic but did not accumulate in the brain. Liposomes injected i.v. did not accumulate in the brain, either. Thus, neither i.v. nor intracarotid administration of liposomes produce results suitable for therapy of brain tumors/metastases.

In order to develop the transdermal formulations of morphine hydrochloride with high skin permeation rate and prolonged action, several gels and patches containing potent penetration enhancer, laurocapram (Azone), were prepared. Since there was a long lag time period for morphine permeation through the excised hairless rat skin in Azone treatment, N-methyl-2-pyrrolidone was added to the Azone gel or patch as a co-enhancer to increase the skin permeation of morphine hydrochloride, especially in the early phase. The mixed solvent of N-methyl-2-pyrrolidone and water showed cosolvency of morphine hydrochloride, and the co-enhancer could shorten the lag time period of skin permeation of morphine hydrochloride. However, the co-enhancer alone had little effect on the skin permeation of morphine hydrochloride. It was effective only when using with Azone. Coadministration of Azone with the co-enhancer showed high in vitro skin permeation and in vivo blood level of the drug. A marked analgesic effect was found after application of morphine hydrochloride patch containing Azone and N-methyl-2-pyrrolidone. The pharmacological effect was much more prolonged than that after the conventional s.c. injection. From these results, it was predicted that the topical formulations of morphine hydrochloride containing Azone and N-methyl-2-pyrrolidone might be useful for the relief of severe chronic pain in patients.

This study was designed to test whether previously untreated patients with head and neck cancer could effectively manage home continuous infusion chemotherapy, and to compare their acceptance and adjustment to home versus inpatient treatment. Twenty-two patients received 3-4 cycles of induction chemotherapy and a 5-day continuous intravenous infusion (CVI). Patients were randomized to receive the CVI portion of cycle 1 either in the hospital via a standard chemotherapy delivery device or at home via the Travenol Infusor, a portable and disposable drug delivery system. For their second cycle of chemotherapy, patients crossed over to the alternate drug delivery method. Patients who did not want to receive their treatment at home received their chemotherapy as inpatients via the Infusor. Therefore, all patients received treatment with both drug delivery methods. Nineteen patients were evaluable for this study. Eleven patients received at least one cycle of home CVI chemotherapy, and adjusted well to this method of drug delivery. Levels of psychological distress decreased for this group of patients when receiving outpatient chemotherapy compared to their inpatient cycles. The eight patients who received all chemotherapy cycles as inpatients (refused home treatment) were found to be less educated and reported greater physical impairment prior to study entry than future home CVI acceptors. Levels of psychological distress in this group increased with each inpatient chemotherapy cycle. We conclude that home CVI chemotherapy may be an alternative to inpatient treatment for patients who have had at least one cycle of inpatient chemotherapy. The best candidates for home treatment are patients with unimpaired daily functioning and a minimum high school education.

The targeted delivery to cells by liposomes and leakage under delivery conditions of fluorodeoxyuridine (FdUR) and fluorodeoxyuridine monophosphate (FdUMP) have been evaluated using a two-compartment growth inhibition assay. Under cell culture conditions, FdUR leaks 100% from all liposomes regardless of charge or phase transition temperature. Under the same conditions, FdUMP leaks 100% from egg yolk phosphatidylglycerol liposomes, 47% from distearoylphosphatidylglycerol liposomes, 44% from egg yolk phosphatidylcholine liposomes, and 10% from distearoylphosphatidylcholine liposomes. All liposomes were prepared from a 67:33 mixture of phospholipid and cholesterol. The two-compartment assay demonstrates directly that neither of these drugs is delivered selectively to the target cells by the liposomes, suggesting that they are liposome independent drugs.

Two patients with bilobar liver metastases were characterized by dual arterial blood supply to the liver. Treatment of both patients by the administration of chemotherapy, selectively via the arterial branches supplying the respective hepatic lobes bearing the metastases, resulted in differential tumor regression/progression. Thus, while the metastases borne by the arterially infused lobe regressed, the counterpart in the other (systemically infused) lobe showed marked progression. This phenomenon lends strong support to the notion that arterial infusion of chemotherapy in cases of regionally predominant (or confined) neoplastic disease, i.e., in the liver, is superior to the intravenous administration of similar drugs.

We have evaluated a semiautomated radiometric assay (BACTEC 460 system) for screening of activity of anticancer drugs against human non-small cell lung cancer cell lines. Cells from seven cell lines were exposed to standard antineoplastic agents at four different concentrations using a 1-h incubation. Alpha 2-interferon was tested using a continuous incubation. In vitro drug activity was analyzed as a function of the clinically achievable serum concentration. Our results indicate that two cell lines (CALU-3, SK-MES-1) exhibit in vitro drug sensitivity patterns closest to those observed in clinical studies. These two cell lines might therefore be most useful for screening new anticancer compounds for activity against non-small cell lung cancer. The radiometric assay is a semiautomated system which has advantages over other, more time-consuming screening systems.

We report experiments which test the toxicity of a new potential therapeutic agent, agarose-bound adriamycin (ImA). In C57Bl/6N mice this preparation is almost completely devoid of untoward effects when administered intraperitoneally; ImA lacks all the usual toxic repercussions of free adriamycin including abdominal adhesions, inflammatory peritonitis, weight loss and cardiotoxicity. The immobilized adriamycin is also inactive in a fetal mouse heart model of cardiac toxicity. This lack of toxicity is not due to an intrinsic inactivity of the drug, however, since previous studies have shown that polymer-bound adriamycin can kill actively dividing cells. We also show here that the immobilized drug can undergo redox reactions and interact with enzymes from isolated respiratory chain preparations, so the lack of cardiac toxicity in vivo is most likely due to inaccessibility of the target. These results suggest that polymer immobilized adriamycin lacks the toxicity of the parent compound and may present a useful approach to regional chemotherapy.