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PubMed2000

Calcium antagonists potentiate P-glycoprotein-independent anticancer drugs in chronic lymphocytic leukemia cells in vitro.

BACKGROUND AND OBJECTIVES: A major obstacle to the successful use of chemotherapy in the treatment of leukemia and other cancers is the emergence of drug resistance. One of the most studied resistance mechanisms is mediated by P-glycoprotein, which can be modulated by calcium channel blockers. Here we investigated whether the Ca(2+) channel blockers verapamil and nifedipine are toxic alone and in combination with P-glycoprotein-independent anticancer drugs against chronic lymphocytic leukemia (CLL) cells in vitro. DESIGN AND METHODS: Verapamil cytotoxicity was investigated in peripheral blood samples of 35 patients with B-cell CLL and 10 healthy control subjects. Cytotoxicity was assessed in in vitro 4-day cultures using 14C-leucine incorporation as an indicator of cell viability. Interactions were tested with Ca2+ channel blockers and cyclosporine or 7 anticancer drugs: (i) chlorambucil, (ii) 2-chlorodeoxyadenosine, (iii) cisplatin, (iv) fludarabine, (v) prednisolone, (vi) adriamycin, and (vii) vincristine. The mode of cell death was assessed by annexin binding and DNA ladder formation. RESULTS: Verapamil induced dose- and time -dependent death of CLL cells in vitro. A statistically significant effect (p = 0.0085) was noted with as little as 4 microM verapamil. The mode of cell death was apoptotic as determined by annexin positivity and condensation of verapamil-treated cells. Verapamil effectively potentiated the toxicity of cyclosporine and all the anticancer drugs mentioned above. Furthermore, nifedipine, a more specific L-type calcium channel antagonist, significantly potentiated the effect of chlorambucil against CLL cells. Interpretation and Conclusions. Calcium channel blockers enhance the effect of P-glycoprotein-independent anticancer drugs remarkably. This indicates that the death signals initiated by calcium depletion and anticancer drugs together facilitate cell death. This novel finding opens a new avenue to modulate, by using calcium channel antagonists, the effect of traditional anticancer drugs having different mechanisms of P-glycoprotein-independent action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

[Anticancer properties of flagellate protozoan Trypanosoma cruzi Chagas, 1909].

The anticancer activity of Trypanosoma cruzi has been confirmed by the example of seven strains. Five virulent strains induced the infection, which inhibited sarcoma-180 growth 1.5-22.0 times. The parasites featured tumortropism; i.e., the successfully developed in cancer cells and even preferred them to normal cells. This taxis-based phenomenon was particularly pronounced at cocultivation of the normal and cancer cells. Cultures of the seven (avirulent and virulent) strains can produce an anticancer agent that selectively damages human cancer cells in vitro. The long-term anticancer effect of T. cruzi or preparations from it, as well as possible its cancer preventing effect, has been demonstrated. Three problems are discussed on the basis of the obtained and recently published data: (1) the mechanism of T. cruzi anticancer effect; (2) the nature of the anticancer agent; and (3) the distribution of the considered phenomenon among trypanosomatides. The anticancer activity of T. cruzi may be due to a combination of surface cellular antigens and an inhibiting or lysing factor.

Animals↗

PubMed2001

Apoptosis and anticancer drug resistance.

Anticancer agents induce cancer cell death through apoptosis or necrosis. As anticancer agents at low and high concentrations cause apoptosis and necrosis, respectively, cancer cells may be merely injured by an anticancer agent in apoptosis, and cell death may result from an activation of the internal constituents to induce apoptosis. Therefore, an alternation of apoptotic pathway must change the efficacy of anticancer agents. As an escape of cancer cells from apoptosis seems to be closely associated with the development of anticancer resistance, this report focuses on mechanisms of apoptosis and its association with anticancer resistance. A Bax induces apoptosis mitochondria-dependently, whereas Fas can induce apoptosis mitochondria-independently. An interaction of Bax and Bcl-2 is very important to decide cell life or death, and Bcl-2 phosphorylation may control this interaction: Paclitaxel treatment induced Bcl-2 phosphorylation and typical apoptosis, whereas hyperthermia induced not Bcl-2 phosphorylation but nuclear translocation and failed to induce apoptosis. Moreover, Fas was localized in the cytoplasm of exponentially growing cells and on the cell membrane of confluent cells. We would like to emphasize that it is very important to check the localization of constituents of apoptosis in order to evaluate the susceptibility of cancer cells to apoptosis.

Animals↗

PubMed2004

Combination with water-soluble antioxidants increases the anticancer activity of quercetin in human leukemia cells.

While accumulation of reactive oxygen species (ROS) is believed to be harmful to organisms, recent studies show that quercetin (QU), a promising antioxidant and anticancer drug, exerts its anticancer role through either diminishing or promoting ROS generation under different conditions. In the present study, it was investigated whether the water-soluble antioxidants ascorbic acid (ASA), N-acetyl-cysteine (NAC) and reduced glutathione (GSH) can enhance both the antioxidant and anticancer activity of quercetin in human myeloid leukemia cells (HL-60 cells). Proliferation, viability and ROS accumulation (indicated by the level of malondialdehyde, MDA) was significantly decreased by QU in HL-60 cells. 50 microM H2O2 markedly attenuated the antioxidant and anticancer activity of QU, proving that diminution of ROS accumulation considerably contributes to the QU-induced decrease of HL-60 cells proliferation and viability. When the effects of water-soluble antioxidants were tested, ASA at 1 mM, NAC at 500 microM, or GSH at 250 microM significantly enhanced QU-mediated proliferation arrest, cell death and ROS diminution. These results indicate that certain amounts of ROS are critical for the proliferation and viability of HL-60 cells, while water-soluble antioxidants enhance the anticancer activity of QU through scavenging ROS. Combing QU with water-soluble antioxidants could be a useful strategy to improve the anticancer activity of QU by increasing its antioxidant activity.

Acetylcysteine↗

PubMed2005

Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells.

Curcumin (Cur) is a promising antioxidant and anticancer drug, but several recent studies indicate that Cur exerts its anticancer activity through promoting reactive oxygen species (ROS) generation. In the present study, concentration-dependent regulation of Cur on cell proliferation, viability and ROS generation, and effect of water-soluble antioxidants ascorbic acid (ASA), N-acetyl-cysteine (NAC) and reduced glutathione (GSH) on the antioxidant and anticancer activity of Cur were investigated in human myeloid leukemia cells (HL-60 cells). We found that although Cur concentration- and time-dependently decreased the proliferation and viability of cells, its effect on ROS generation (as indicated by the level of malondialdehyde, MDA) varied with its concentrations. I.e., low concentrations of Cur diminished the ROS generation, while high Cur promoted it. Combined with the opposite effect of 50 microM H2O2 on low or high Cur-induced MDA alteration, cell proliferation arrest and cell death, these results proved that low Cur exerted its anticancer activity through diminishing ROS generation in HL-60 cells, while high Cur through promoting ROS generation. Further studies showed that all water-soluble antioxidants ASA, NAC and GSH significantly enhanced both the antioxidant and the anticancer activity of low Cur. Considering that the extra accumulation of ROS is harmful to normal cells, the data presented here indicate that instead of using high doses, combining low doses of Cur with water-soluble antioxidants is a better strategy for us to improve the anticancer activity of Cur.

Acetylcysteine↗

PubMedDate not supplied

Anticancer versus antigrowth activities of three analogs of the growth-inhibitory peptide: relevance to physicochemical properties.

A 34-amino acid peptide has been synthesized based on an amino acid sequence from the third domain of native full-length alpha-fetoprotein, which has been shown to have both antigrowth and anticancer activities. This peptide, known as the growth-inhibitory peptide (GIP), has two cysteine residues and demonstrates reduced antigrowth activity after long-term storage, presumably due to disulfide bond formation. The disulfide bridge problem was addressed by replacing the two naturally occurring cysteines with either glycines, alanines, or serines (to produce the G-, A- and S-peptides, respectively). The non-hydrophobic G- and S-peptides were found to exist as dimers, while the more hydrophobic C- and A-peptides formed trimers in solution under certain conditions of pH and peptide concentration. The A-peptide was already known to display anticancer activity; however, the G- and S-serine analogs have not been studied in depth since they had demonstrated low antigrowth activities in rodent uterine assays. Using both in vivo and in vitro assays, the A-, G- and S-peptides were shown to exhibit various degrees of cancer growth suppression. An in vitro culture assay, using MCF-7 breast cancer cells, demonstrated that both the G- and S-peptides showed modest cancer growth suppression, while the A- analog showed strong inhibition at doses ranging from 10(-5) M to 10(-7) M. In contrast, an in vivo ascites tumor study of all four peptides showed them to have notable activity in the suppression of mouse mammary tumor growth. Overall, our data indicated that physicochemical properties, such as hydrophobicity, oligomeric state and secondary structure, contribute to the anticancer activity of both the active C- peptide and its analogs. In addition, the antigrowth rodent uterine assay was not always predictive of the anticancer potential of the peptide forms, suggesting a difference between the mechanism of peptide action in the antigrowth models and that in the anticancer assay. Notably, the antigrowth assay failed to predict the marked anticancer activity of the analogs against a mammary tumor, indicating that the growth bioassay cannot always be relied upon as a screening protocol.

Amino Acid Sequence↗

PubMed1986

[Targeting of anticancer chemotherapy utilizing the characteristic nature of the neovasculature of solid tumors].

We have been able to achieve targeting of anticancer treatments using the differences between the neovasculature of solid tumors and the vasculature of normal tissues. The first of these differences was as follows; We discovered that when the lipid contrast medium, Lipiodol, was administered arterially, it remained selectively in the solid tumor for a long time. Using this characteristic nature of Lipiodol, we achieved targeting of anticancer chemotherapy by arterial administration of oily anticancer drugs solubilized in Lipiodol. Remarkable anticancer effects against various malignant solid tumors were observed using this targeting chemotherapy. The second of the above differences, studied by Suzuki, is responsiveness to angiotensin II, in which the blood flow in the tumor can be increased using this vasoconstrictor. With Angiotensin II, a larger volume of oily anticancer drugs could be delivered to the tumor. The third difference is the permeability of the neovasculature to drugs of high molecular weight and the duration that these drugs remain in the extracapillary space. The high-molecular-weight anticancer agent, SMANCS (m.w. 17,000) dissolved in 5% glucose solution, was administered intravenously, and its histological antitumor effects on gastric cancer and esophageal cancer were clearly observed.

Angiotensin II↗

PubMed1989

[Comparative study on the anticancer activities of KW2149 and mitomycin C against human tumor xenografts using subrenal capsule assay].

The anticancer activity of KW2149, a new derivative of mitomycin C (MMC), was investigated against 5 human tumor xenografts derived from digestive organs using 4-day subrenal capsule assay (SRCA). Normal immunocompetent mice were used in this assay. For the comparative study, KW 2149 and MMC were administered intraperitoneally for 3 days after implantation, and the anticancer activity and the weight loss of mice were evaluated. The total doses were determined as 1/2, 1/3 and 1/4 of LD50 value of each anticancer agent. The anticancer activities of the two drugs were almost the same with no significant difference in 3 xenografts. Thus, it may be suggested the difference of the anticancer spectrum between the two drugs. The anticancer activity of KW2149 indicated higher correlation with the administered doses as compared with MMC. The toxicity of KW2149 was almost the same as MMC according to the weight loss of mice.

Animals↗

PubMed1989

[Loco-regional cancer chemotherapy with a new drug delivery system, "anticancer drug-fibrin clot"].

Five different types of anticancer drugs were individually entrapped into fibrin clots using our own material, "G.T.XIII" to provide an "anticancer drug-fibrin clot" for regional cancer chemotherapy. Anticancer drugs used in the present study were ADM, MMC, MTX, 5-FU and cDDP. The release of drugs from fibrin clots was studied in vitro. Each fibrin clot was intraperitoneally administered to cancer (AH-130)-bearing rats to evaluate the oncolytic effects. The activities of anticancer drugs delivered from the clots were maintained for more than two weeks. Survival terms of cancer bearing rats were remarkably prolonged with the anticancer drug-fibrin clots. Neither recurrence of ascites nor metastases of malignant cells was observed in the rats treated with such clots. Our newly devised anticancer drug-fibrin clots showed a sustained release of oncolytic drugs and favorable antineoplastic effects. This newly devised drug delivery system suggested a clinical potential for regional cancer chemotherapy.

Animals↗

PubMed1988

[Targeting cancer chemotherapy using lipiodol as a carrier of anticancer drugs for hepatocellular carcinoma].

We have found that the lipid lymphographic agent, Lipiodol ultrafluid, remains selectively in hepatocellular carcinoma and other malignant solid tumors. Lipiodol administered arterially flows into the normal blood vessels of normal tissues and into the neovasculature of the tumor. Selective retention of Lipiodol in the tumor occurs due to early removal from the normal blood vessels and retention in the neovasculature and extravascular space in the tumor. Using this characteristic nature of Lipiodol, targeting cancer chemotherapy was achieved. It was shown that anticancer drugs had to be dissolved in Lipiodol and diffuse out gradually from the agent in order to achieve targeting cancer chemotherapy. Various kinds of oily anticancer agents which facilitate targeting cancer chemotherapy, such as SMANCS/Lipiodol, mitomycin/Lipiodol, adriamycin/Lipiodol and aclarubicin/Lipiodol were successfully developed. Clinically, these oily anticancer agents were administered to 260 patients with hepatocellular carcinoma. Selective long-lasting retention of Lipiodol in hepatocellular carcinoma was proved on the basis of CT and low-kVp X-ray examination, and persistent high biological activities of anticancer drugs in the tumor were also recognized. The serum AFP level and tumor size showed a decrease in 92% and 90% of cases, respectively. The survival period of these patients with unresectable tumor treated with this protocol was definitely longer than in the comparison group, i.e., the 50% survival period for the comparison group was 1.3 months, while that of the patients who received this protocol was 13 months. In patients administered a SMANCS dose of more than 0.25mg/cm2 of maximum cut-surface area, complete necrosis of the tumor was found, and importantly, non-cancerous liver tissue remained unaffected. Neither hematosuppression nor any severe side effects due to anticancer drugs were observed. Remarkable antitumor effects and reduced side effects could thus be achieved by targeting chemotherapy using Lipiodol as a carrier of anticancer drugs.

Antineoplastic Agents↗

PubMed1987

[Targeting chemotherapy of hepatocellular carcinoma by arterial administration of anticancer agents dissolved in lipiodol].

The lipid lymphographic agent, Lipiodol ultrafluid has been found to remain selectively in hepatocellular carcinoma. Using this characteristic nature of Lipiodol, a new targeting anticancer chemotherapy was devised. In order to achieve targeting anticancer chemotherapy and useful anticancer effects, anticancer drugs must be dissolved or suspended in Lipiodol and diffuse out from the Lipiodol gradually. Oily anticancer agents such as SMANCS dissolved in Lipiodol (SMANCS/Lipiodol), Mitomycin C in Lipiodol (MMC/Lipiodol), Aclarubicin in Lipiodol (ACR/Lipiodol) and a mixture of these were administered by catheterizing the celiac or hepatic artery under X-ray monitoring in 216 patients with hepatocellular carcinoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in 91% of cases. The survival period of patients with unresectable hepatoma treated with the present protocol was definitely longer than the comparison group.

Aclarubicin↗

PubMed1984

[clinicopathological study on gastric carcinoma following preoperative anticancer chemotherapy].

Clinicopathological study was undertaken on gastric carcinoma, 130 cases and 145 lesions, treated with preoperative anticancer chemotherapy, using Oboshi-Shimosato's criteria for histologic grading of effects. The results were as follows: Not only morphologic manifestations observed by X-ray and endoscopy, but also histopathologic findings of biopsied specimens taken after treatment with 5-FU for 12 consecutive days, were effectively used for judging the sensitivity of cancerous tissue to anticancer agents in vivo. Effective rates were high in cases treated with oral administration of 5-FU more than 500 mg/day and 5.0 gr as a total dose (p less than 0.01), and the incidence of anticancer-induced-gastritis was also seen high in cases with oral administration of 5-FU more than 500 mg/day and 6.0 gr as a total dose (p less than 0.005). The proper dosage of 5-FU orally administered was, therefore, 500 mg/day and 5.0 gr. as a total dose. Histologic effects of anticancer agents on primary lesions were in accordance with those of metastatic foci of lymph nodes (p less than 0.01). 5-FU when orally administered resulted in a low rate of significant toxicity (23.5%), and no serious side-effects. In conclusion, it is considered that preoperative anticancer chemotherapy on gastric carcinoma apparently causes cancer cell death, decrease viability of cancer cells, makes it possible to detect in-vivo sensitivity for anticancer agents, and will improve the late survivals of patients with gastric carcinoma.

Adenocarcinoma↗

PubMed1982

[Treatment of brain tumors with anticancer pellet--experimental and clinical study (author's transl)].

Eighty three patients suffering from brain tumors have been treated by anticancer pellets containing 5-FU, urokinase, mitomycin and BUdR in dimethylsiloxan (Silastic) for three years. Constant and prolonged release of the chemicals from the anticancer pellet had already been proved in vitro. The amount of daily release were 1-3/1,000 of original volume. Tissue concentration of 5-FU was measured by bioassay system using staphylococcus 209 P strain with plate dilution method. In spite of the rapid disappearance of serum 5-FU, the local high accumulation of 5-FU was demonstrated in vivo. In rat neurogenic tumor, 1.104 microgram/g was detected on 60 days after the application of anticancer pellet containing 500 mg of 5-FU. The growth of tumor was also suppressed. The clinical study consists of 83 patients, 30 of glioblastoma, 19 of metastatic brain tumor, 13 of astrocytoma, 7 of oligodendroglioma, 4 of ependymoblastoma, 4 of malignant lymphoma and 6 of others. The median survival time of gliblastoma was prolonged to 71.5 weeks by the implantation of anticancer pellet from 40 weeks of control group. However, the median survival time of astrocytoma and metastatic brain tumor were 24 and 6 months, respectively, which have no significant difference from control groups. In the patients of metastatic brain tumor, the regrowth of metastatic foci in the brain was completely suppressed. However, most of them were succumbed from the original tumors. The concentration of 5-FU in several human tissue was measured in ten patients with different time intervals after the implantation of the anticancer pellet. Although they have different histologic patterns, the concentrations of 5-FU in human brain tumors were ranged from 0.05 to 0.67 microgram/g by 14 months after the implantation of the anticancer pellet. The adjacent cystic fluids also contain from 0.62 to 4.9 microgram/ml of 5-FU for two years. These results mean that they are keeping higher level of 5-FU than the tumoricidal level of 5-FU (0.056 microgram/g) for more than two years. On the other hand, no respective accumulation was demonstrated in other tissues. None of the patients showed any adverse reactions except a continuous slight fever up to 38 degrees C.

Adult↗

PubMed1980

Effect of anticancer agents on the susceptibility of tumor cells to immune cytolysis.

Effect of anticancer agents on the immune cytolysis of tumor cells was investigated. Cell of ascites hepatoma line of C3H/He strain of mouse, MH134, were treated with anticancer agents and used for target cells in immune cytolysis experiments. In cytotoxicity tests, MH134 cells pretreated with mitomycin C or Adriamycin were lysed by xenogeneic or allogeneic antisera and complement at significantly higher rates than non-treated MH134 cells. To test cytostatic effect of antisera, target MH134 cells were pretreated with much lower concentration of anticancer agents than that in the cytotoxicity tests, the anticancer-agent-treated tumor cells were damaged with complement and the xenogeneic and allogeneic antisera at higher rates than the non-treated tumor cells. Allogeneic spleen cells from DDD mice sensitized with MH134 tumor damaged anticancer-agent-treated MH134 cells at higher rates than non-treated MH134 cells. These results suggested an enhancing effect of anticancer agents on immune cytolysis of tumor cells in hosts who could actively and/or passively immunologically respond against tumor.

Animals↗

PubMed2001

Chemistry and chemical biology of taxane anticancer agents.

Taxol (paclitaxel) and Taxotere (docetaxel) are currently considered to be among the most important anticancer drugs in cancer chemotherapy. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e., causing mitotic arrest in cancer cells, leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesirable side effects, as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with superior pharmacological properties, improved activity against various classes of tumors, and fewer side effects. This paper describes an account of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface, including: 1. The structure-activity relationship (SAR) study of taxoids leading to the development of the "second-generation" taxoids, which possess exceptional activity against drug-resistant cancer cells expressing the MDR phenotype. 2. Development of fluorinated taxoids to study the bioactive conformation of paclitaxel and photoaffinity labeling taxoids for mapping of the drug-binding domain on both microtubules and P-glycoprotein. 3. The synthesis of novel macrocyclic taxoids for the investigation into the common pharmacophore for microtubule stabilizing anticancer agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

IL-2 perfusion to the liver augments the hepatic extraction rate of accompanying anticancer drugs.

A pilot study we conducted on hepatic infusion chemotherapy combined with interleukin-2 (IL-2) for metastatic liver malignancies revealed very encouraging results indicating that this treatment modality is more effective than either of the anticancer drugs used alone. To clarify the mechanisms underlying the synergism of these modalities, the pharmacokinetics of anticancer drugs were examined in a rat model. Adult rats were given 5-fluorouracil (5-FU) or mitomycin C (MMC) combined with various doses of IL-2 up to 7500 JRU/kg per minute for the measurement of hepatic extraction rates (HER). The HER of 5-FU was significantly increased (P < 0.01) in combination with IL-2 in a dose-dependent fashion while that of MMC also showed a tendency to increase. Thus, it is conceivable that the increase of vascular permeability caused by IL-2 results in augmentation of the HER of associated anticancer drugs. This effect may improve the delivery of anticancer drugs to the liver and alleviate general toxicity by reducing the amount of circulating anticancer agents.

Animals↗

PubMed2002

Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy.

Apoptosis is an important phenomenon in cytotoxicity induced by anticancer drugs. Here, we review the current status of the molecular mechanisms of anticancer drug-induced apoptosis in order to assess the contribution of molecular-level analysis to cancer chemotherapy. It is apparent that the molecular mechanisms by which anticancer drugs induce apoptosis are mediated by death receptor-dependent and -independent pathways, which are related to the release of cytochrome c through voltage-dependent anion channels in the mitochondrial inner membrane. The release of cytochrome c is the central gate in turning on/off apoptosis, and is regulated by the interaction of proapoptotic proteins, including Bid, Bax and Bak, and antiapoptotic proteins including Bcl-2 and Bcl-X(L), and a specific class of inhibitors of apoptosis proteins (IAPs) including Akt, survivin, and heat-shock proteins. The caspase cascade is activated by the release of cytochrome c, which is initiated by the formation of apoptosomes consisting of procaspase-9, Apaf-1 and cytochrome c in the presence of dATP, and results in the activation of caspase-9 and caspase-3, thereby leading to apoptosis. Drug sensitivity can be enhanced by the introduction of proapoptotic genes and the inhibition of antiapoptotic proteins. The latter process is mediated by antisense oligonucleotides and is associated with apoptosis. The signal transduction pathways that are triggered by the central gate in mitochondria play a critical role in anticancer drug-induced apoptosis. The modulation of signal transduction pathways targeting the proteins involved in these signal transduction pathways using antisense IAPs, and growth factor antibodies may be a good strategy for enhancing therapeutic efficacy of anticancer drugs in cancer chemotherapy.

Antineoplastic Agents↗

PubMed2001

Treatment of VX2 carcinoma implanted in the liver with arterial and intraperitoneal administration of oily anticancer agents.

PURPOSE: Long-term survival and cure cannot be achieved in patients with unresectable, advanced abdominal cancer, because no chemotherapeutic treatment has definite antitumor activity for malignant solid tumor and its dissemination. In this study, arterial and intraperitoneal administration of oily anticancer agents, which have properties that permit targeted chemotherapy for VX2 carcinoma implanted in the liver, was attempted to achieve long-term survival. MATERIALS AND METHODS: Rabbits bearing VX2 tumors in the liver measuring 1-2 cm in diameter received an arterial injection of 0.2 ml of nitrogen mustard N-Oxide (HN2-O) dissolved in Lipiodol (7.5 mg/ml), a newly developed oily anticancer agent, for the tumor and an intraperitoneal injection of a cocktail of oily anticancer agents for the prevention of intraperitoneal dissemination. RESULTS: Twelve out of thirteen rabbits survived and VX2 cancer was not observed in these 12 rabbits. The controls received a sham operation, an intraperitoneal injection of the cocktail of oily anticancer agents alone, or an arterial injection of HN2-O/Lipiodol alone. In these control groups, 27 out of 29 rabbits died of cancer. To examine the dose form for arterial injection, 14 rabbits received an arterial injection of the simple mixture of HN2-O dissolved in physiological saline and Lipiodol, with an additional intraperitoneal injection of the cocktail. Eight of these 14 rabbits died of enlargement of the hepatic tumor and peritoneal dissemination. CONCLUSION: Long-term survival and cure was achieved in almost all rabbits bearing VX2 tumor in the liver by simultaneous arterial and intraperitoneal injection of oily anticancer agents.

Animals↗