Selective cancer therapeutics最新文献

Intraperitoneal (i.p.) chemotherapy is being investigated as an adjunct to surgery to kill residual cancer cells, inhibit cancer cell seeding, local recurrence, and metastases for ovarian, gastric, and colon cancers. In this report, the therapeutic effects of Doxorubicin (Dox) and liposome-entrapped Dox (Dox-Lip) against i.p. mouse colon 26 (C26) tumor were compared. It was found that Dox-Lip was less toxic than Dox after i.p. administration in non-tumor bearing animals. I.P. Dox and Dox-Lip significantly inhibited the growth of C26 tumor when the treatment was initiated 1 day after tumor cell inoculation, but both administration forms were ineffective against well-established (8-day) tumors. Multiple dose schedules did not improve the therapeutic response. Dox-Lip was not therapeutically superior to Dox at equal doses or at approximately equi-toxic doses. In addition, the relative retention of Dox and Dox-Lip in the peritoneal cavity and their plasma pharmacokinetics were investigated. It was found that Dox levels in the peritoneal cavity were maintained for longer periods after i.p. Dox-Lip was administered. However, the results show that maintenance of elevated drug levels in the peritoneal cavity does not necessarily lead to increased therapeutic effects.

The ability of RO 11-2933 to modulate in vivo Doxorubicin and Cisplatin antitumor activity has been evaluated in sensitive and resistant P388 and L1210 murine leukemias. A reversal of both Doxorubicin or Cisplatin resistance has been observed when P388/Dx or L1210/CP tumor bearing mice received multiple treatments of the antitumor agent plus 30 mg/Kg of RO 11-2933. No modification of Doxorubicin or Cisplatin effect has been observed in sensitive tumors. The results obtained indicate that RO 11-2933 might represent a promising agent for the reversal of multidrug resistance.

Several halogenated analogs of thymidine and cytidine possess antineoplastic and antiviral activity. They are also powerful sensitizers of bacterial and mammalian cells to lethal effects of x-irradiation. An important factor limiting the effectiveness of these agents in therapy is their extremely short half-life in circulation due to rapid hepatic dehalogenation. An approach to this problem is to deliver the drug directly to its target using monoclonal antibodies. This study evaluates the lysosomotropic delivery systems of halogenated pyrimidines using 5-iodo-2'-deoxyuridine [IUdR] as a model. IUdR, derivatized and activated at either the 3'- or the 5'-position forms covalent adducts with the epsilon-amino groups of the lysine residues in proteins (bovine serum albumin [BSA], and immunoglobulins [IgG]). Two methods suitable for conjugation of IUdR to proteins involving either the formation of acyl-imidazoles in the reaction of IUdR succinates with N,N'-carbonyldiimidazole or the preparation of N-succinimidyl esters of IUdR succinates were established. Both derivatives express comparable reactivity toward proteins. The degree of IUdR incorporation is easily controlled by the ratio of reagents. The succinate "arm" linking IUdR to protein is susceptible to lysosomal hydrolysis in vitro releasing intact IUdR. The half-life of the IUdR-IgG conjugate in the presence of the lysosomal enzymes was shown to be approximately twice that of the IUdR-BSA conjugate.

We synthesized the 3',5'-O-dipalmitoyl derivative of 5-fluoro-6-[3H]-2'-deoxyuridine and incorporated it into the bilayers of multilamellar liposomes (400 nm diameter) of various lipid compositions. The prodrug-containing liposomes were incubated with rat liver macrophages (Kupffer cells) in monolayer culture and with lysosomal fractions from whole rat liver homogenates. The release of water-soluble radioactive degradation products from the cells was measured and we found the rate of release strongly dependent on the lipid composition of the liposomes. After 4 hours of incubation the release of radioactivity was 9-fold higher from egg-phosphatidylcholine/phosphatidylserine/cholesterol liposomes than from distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol/cholest ero l or dioctadecyl-sn-glycero-phosphorylcholine/dipalmitoylphosphatidylg lycerol/ cholesterol liposomes. A somewhat less pronounced difference in rate of prodrug degradation was found when the liposomes were incubated with lysosomal fractions. The water-soluble products that were formed showed anti-tumor activity against C26-adenocarcinoma tumor cells in vitro. Preliminary evidence suggests this activity to be caused by 5-fluoro-2'-deoxyuridine. We conclude that incubation of liposomes of varied composition containing diacylated 5-fluoro-2' deoxyuridine derivatives with Kupffer cells in culture, results in the formation of an intracellular prodrug depot in these cells from which compounds with anti-tumor activity are released with controllable rates.

Vinblastine sulfate (VLB) suspended within a collagen matrix (CM) as a diffusion limiting drug delivery vehicle was examined in vitro, as well as in mouse subcutaneous and brain tumor models. Against RIF-1 and KHT subcutaneous tumors, there was enhancement of antitumor activity with intratumoral (i.t.) delivery of VLB when it was combined with CM and/or epinephrine (epi) provided as a vasoactive agent to limit diffusion of VLB away from the injection site. Furthermore, in pharmacokinetic studies an 3-fold enhancement of tumor exposure to drug (AUC) with the CM-formulation was observed relative to the administration of free VLB i.t. Craniotactic injection of VLB into mouse brain in doses from 0.2 to 2 mg/kg revealed that the CM association markedly reduced the acute toxicity of VLB in normal mouse brain. Furthermore, mice with stereotactically implanted KHT brain tumors treated with 0.2 mg/kg VLB in CM had less tumor present in the brain histologically compared to the free VLB and untreated control groups.

Utilizing the P388 murine leukemia cells sensitive (P388/S) and resistant (P388/ADR) to Adriamycin (ADR), we evaluated the effect of quinidine, an anti-arrhythmic agent, on the cytotoxic activity of ADR and Mitoxantrone (MITO), both in vitro as well as in vivo. Quinidine enhanced the cytotoxicity of both ADR and MITO in P388/S and P388/ADR cells, as assessed by the decrease in color intensity of formazan crystal in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. A dose dependent inhibition of 3H-thymidine and 3H-uridine incorporation was observed when the P388/S and P388/ADR cells were exposed to quinidine alone. A non-toxic concentration of quinidine (5 microM) enhanced the DNA biosynthesis inhibition induced by ADR (55 to 65%) and MITO (37 to 44%) in P388/ADR cells, indicating reversal of resistance, while in P388/S cells only a minimal increase in DNA biosynthesis inhibition was observed. The combination of quinidine at doses of 50 to 100 mg/kg significantly potentiated the antitumor activity of ADR and MITO in P388/ADR bearing mice, whereas the potentiation of ADR and MITO antitumor response was lower in P388/S bearing mice. Quinidine increased the cellular levels of ADR by 53 to 126% in P388/ADR cells in vitro, but failed to indicate such elevated levels of cellular ADR in P388/S cells. This enhanced intracellular accumulation of ADR in P388/ADR cells, explains the therapeutic efficacy of ADR and MITO in P388/ADR, both in vitro as well as in vivo. Results suggest the efficacy of quinidine to ameliorate the antitumor effects of ADR and MITO in drug resistant tumor cells.

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.