Synergistic Anti-glioma Effects in Vitro and in Vivo of Enediyne Antibiotic Neocarzinostatin and Paclitaxel via Enhanced Growth Delay and Apoptosis-Induction.

Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.

[Hepatocellular carcinoma with multiple lung metastasis resulting in long-term disease-free survival by transcatheter arterial infusion chemotherapy of SMANCS].

The patient was a 61-year-old female with alcoholic liver cirrhosis, who was admitted to our hospital due to elevation of AFP.During the evaluation, both abdominal ultrasound and enhanced abdominal CT revealed a hepatocellular carcinoma measuring 4 cm in the S6-7 region, complicated with an arteriovenous shunt.Additionally, the lung CT examination showed 20 isolated bilateral lung tumors, all of which were less than 1.4 cm in diameter. Following the diagnosis, we performed a transcatheter arterial infusion chemotherapy of SMANCS at 3 mg through the right heptic artery. Thereafter, the AFP level returned to normal. Additionally, the tumors previously observed in both liver and lung, and exhibited by both lung CT and enhanced abdominal MRI, had disappeared.The patient has been in clinical remission more than 10 years to date.

Therapeutic treatment of New Zealand mouse disease by a limited number of anti-idiotypic antibodies conjugated with neocarzinostatin.

-81 and NE-1 idiotypes (Id) of human nephritogenic anti-DNA antibodies are interspecies Id expressed also in NZB/W F1 mice. We tried to manipulate the synthesis of spontaneously occurring anti-DNA antibody using monoclonal anti-Id antibodies (D1E2 and 1F5) conjugated with a cytotoxic agent, neocarzinostatin (NCS). In vivo administration of anti-Id antibodies conjugated with NCS brought about an improvement in the survival rate of female NZB/W F1 mice. It also caused a retardation of development of lupus nephritis and decreased the numbers of anti-DNA-producing cells. The suppression of anti-DNA antibody synthesis was specific and Id-mediated. The results indicate that the use of a limited number of anti-Id antibodies in combination with a cytotoxic agent may be applicable therapeutically to autoimmune diseases.

A facile method of purification of neocarzinostatin, an antitumor protein.

A three-step column chromatographic method for the purification of neocarzinostatin (NCS) from a crude preparation was described. The purified material was homogeneous by acrylamide gel electrophoresis, isoelectric focusing, amino terminal analysis, and immunologic criteria. Purified NCS was 40 times as active in the inhibition of growth of Sarcina lutea and twice as active against CCRF-CEM human leukemia cells in vitro as was the starting material. When assayed against P388 and L1210 mouse leukemias in vivo, the purified material showed a median increase in life-span of 119 and 72%, respectively.

Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image.

Highly malignant rabbit tumor (VX-2) was implanted at the periphery of the liver in 63 rabbits. Selective delivery of the anticancer agent copoly(styrenemaleic acid) conjugated to neocarzinostatin (SMANCS), which was dissolved in an oil contrast medium (Lipiodol), was performed by injection via the proper hepatic artery. The anticancer effect was also evaluated by various parameters. By using low-kVp X-ray examination of the resected rabbit liver, Lipiodol was found to distribute throughout the entire liver arterial lumina and was retained there for about 24 hr, but disappeared from the normal liver arterial lumina gradually. However, Lipiodol was retained in the tumor tissue and vessels for at least 7 days, whereas it was undetectable in any other organs. A radioactive analogue of Lipiodol, a chloroiodinated fatty acid, was prepared by using [14C]linoleic acid. This analogue was used in the study of the distribution by low-kVp X-ray examination, Sudan III staining, and autoradiography. Lipiodol remained in the tumor vessels as well as the tumor cells. The use of the radioisotope yielded a quantitative profile of Lipiodol accumulation in tumor tissues; approximately 1000 times more at 15 min and 100 times more at 3 days after the injection than that of most other organs or plasma. Its major excretion route appeared to be through the bile and then the feces. The biological activity of SMANCS was also determined and was found to be significant in both tumor and liver even 7 days after injection. No activity was found in any other organ or tissue. The relatively high biological activity of SMANCS in the nontumorous liver adjacent to the tumor may be the result of continuous drug release from SMANCS-Lipiodol in the tumor tissue. By histological examination, massive tumor necrosis and infiltration of the inflammatory cells were found in the rabbits treated with SMANCS-Lipiodol. In the rabbits treated with Lipiodol alone, necrosis of the tumor was only minimal, and no infiltration of inflammatory cells was observed. Survival periods of the treated rabbits (n = 14) were significantly longer than those of controls (n = 10); 23.1 +/- 5.5 (S.D.) days versus 16.1 +/- 2.9 days (p less than 0.005), respectively, even though only one injection was used for this highly malignant tumor. Mean tumor size for both groups at laparotomy was 163.3 +/- 83.0 sq mm and 160.5 +/- 76.5 sq mm, respectively (not significant).(ABSTRACT TRUNCATED AT 400 WORDS)

Antitumor effects of SMANCS on rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene.

We previously found that a high-molecular-weight anticancer agent, polystyrene-co-maleic acid conjugated neocarzinostatin (SMANCS), in which two chains of styrene/maleic acid copolymer are conjugated to the anticancer protein neocarzinostatin (NCS), accumulated more selectively in tumor tissue than in normal tissue and was more stable than NCS in blood. These results indicate that SMANCS should have less systemic toxicity and a better therapeutic effect than NCS. In this study, the antitumor activity and adverse effects of SMANCS were compared with those of NCS by using rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene. When tumors of rats, that had received 7,12-dimethylbenz[a]anthracene (20 mg/kg, one dose, p.o. in oily formulation), became palpable usually after 4-20 weeks, SMANCS treatment was initiated. Thirty days after i.v. administration of SMANCS (0.1 mg/kg 3 times and 0.3 mg/kg 3 times), tumors had shrunk in 35 of 37 rats (a mean weight was about 10% of control value; or decreased to about 30% of the value of before treatment in tumor weight); tumor size had not changed in 1 rat, and in the remaining 1 rat the tumor had enlarged. Thirty days after i.v. administration of NCS, tumors had shrunk in 8 of 14 rats, but the tumor size was unchanged in 1 rat and was enlarged in 5. In the control group, all tumors had enlarged. Development of new tumors was completely prevented by the administration of SMANCS. Histological examination of sequential slices of tumor revealed clear finding of degeneration and tumor encapsulation at 30 days after initial administration of SMANCS, with an accompanying fatty degeneration, but these effects were not observed for tumors treated with NCS. Although red blood cell counts and hemoglobin amounts decreased significantly in rats receiving NCS, no such effects were apparent in the SMANCS group.

Local administration of monoclonal antibody-drug conjugate: a new strategy to reduce the local recurrence of colorectal cancer.

This report investigates the application of monoclonal antibody A7 and its drug conjugate in locally controlling colorectal cancer. The experimental protocol consisted of local retention, lymphatic delivery, normal organ distribution, systemic toxicity, and tumoricidal effects. When 125I-labeled monoclonal antibody (Mab) A7 was injected into the pelvis and the thigh of Balb/c mice, a high local retention unrelated to antigen-antibody interaction was observed at the injected site for 24 h after injection. An analysis of local retension properties related to antigen-antibody interaction, conducted by intratumorally or peritumorally injecting 125I-Mab A7 into the tumor-bearing athymic nude mice, revealed a significantly higher tumor localization of Mab A7 in comparison to i.v. injection. 125I-Mab A7 accumulated to a great extent in the ipsilateral regional lymph node but not in the contralateral regional lymph node. Normal organ accumulation of Mab A7 was lower in the locally injected group than in the i.v. injected group. Intratumoral injection of Mab A7-neocarzinostatin (A7-NCS) led to the complete remission of established tumor in 5 of 6 antigen-positive xenograft-bearing mice but exhibited a complete remission in only 1 of 6 antigen-negative xenograft-bearing mice. A single local injection of A7-NCS inhibited tumor development in 12 of 16 and 5 of 15 antigen-positive tumor-bearing mice and antigen-negative tumor-bearing mice, respectively, whereas neither a systemic injection of A7-NCS and NCS nor a local injection of NCS and saline had a notable inhibitory effect on tumor development. Systemic toxicity of NCS was markedly reduced when it was locally administered in the antibody-conjugated form. These findings indicate that local injection of immunoconjugate is a promising new field for controlling the local recurrence of colorectal cancer.

A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.

Reduction of hepatic metastases in rabbits by administration of an oily anticancer agent into the portal vein.

We studied a prophylactic chemotherapy against hepatic metastases arising from the shedding of tumor cells into the portal circulation. The therapy was done with a lymphographic oily contrast medium, Lipiodol, and a high molecular weight anticancer agent named poly(styrene-maleic acid) copolymer conjugated neocarzinostatin (SMANCS), developed in our laboratory. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). Twelve rabbits were simply inoculated with the highly malignant carcinoma VX-2. Fifteen rabbits were given injections of SMANCS in glucose and Lipiodol into the portal vein and were subsequently inoculated with the tumor cells. Eighteen were given injections of SMANCS/Lipiodol and then the tumor cells. These rabbits were killed 12 days later. Thirteen were given injections of the tumor cells alone and were allowed to survive. Sixteen were given injections of SMANCS/Lipiodol and then with the tumor cells; they were allowed to survive. Rabbits given injections of SMANCS/Lipiodol before tumor inoculation had significantly fewer (P less than 0.001) metastases than those not treated or those given SMANCS in glucose and Lipiodol. Survival was significantly longer [P less than 0.005; 36.0 +/- 7.7 (SD) days] with SMANCS/Lipiodol before tumor inoculation than without treatment [23.5 +/- 3.0 days]. SMANCS/Lipiodol has a prolonged anticancer effect because it remains in the portal vein and allows sustained drug release from the oil (Lipiodol) to aqueous spaces. Hepatic metastases might be prevented by portal administration of the appropriate oily anticancer agent.

Changes in cellular components of spleen and lymph node cells and the effector cells responsible for Meth A tumor eradication induced by zinostatin stimalamer.

We reported previously that pretreatment with zinostatin stimalamer (ZSS) eradicated Meth A tumors in BALB/c mice. We herein investigated cellular components of spleen and lymph node cells of Meth A-bearing ZSS-pretreated mice by flow cytometry; the antitumor effector cells by in vivo depletion of T cells, NK cells, or macrophages; and host-mediated antitumor activity associated with ZSS treatment after tumor transplantation. ZSS given on day-3 transiently decreased the number of spleen cells. The percentage of T cells increased, but B cells and macrophages decreased. B cells decreased in inguinal lymph nodes in Meth A-bearing ZSS-pretreated mice, but increased in Meth A-bearing control mice. In vivo depletion experiments using antibodies or carrageenan showed that antitumor effector cells for tumor eradication are Thy1.2+/Lyt2.2+ and that at least a part of them are asialo GM1+. Thy1.2+/Lyt2.2+/asialoGM1- cells are important in generation of the antitumor activity of ZSS; however, L3T4+ T cells are also involved in initiation of tumor eradication. The result of ZSS treatment after tumor transplantation suggests that ZSS might exhibit antitumor activity by augementating host-mediated antitumor resistance, as well as its intrinsic cytocidal activity.

Neocarzinostatin versus m-AMSA or doxorubicin in hepatocellular carcinoma.

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).

SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy.

This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy, in particular the development and use of SMANCS, a conjugate of neocarzinostatin and poly(styrene-comaleic acid). The various topics covered include a brief description of the chemistry and polymer conjugation, the binding of the conjugate to albumin and the biological behaviour in vitro and in vivo after arterial injection in animals, including plasma half-life, and the lipid solubility of SMANCS in medium chain triglycerides and Lipiodol, a lipid contrast medium suitable for use in X-ray-computed tomography. The biological response-modifying effects and the tumor-targeting mechanism of SMANCS and other macromolecular drugs are also discussed. The latter mechanism is accounted for in terms of a tumor 'enhanced permeability and retention' (or EPR) effect. A principal advantage in the use of SMANCS or other macromolecular drugs is the potential for a reduction or elimination of toxicity. Macromolecular drugs such as a pyran copolymer-NCS conjugate show a marked reduction in bone marrow toxicity normally associated with the use of NCS. This is believed to be due to a hypothetical blood-bone marrow 'barrier' which, relative to NCS, restricts or limits access of the macromolecular drug to the bone marrow. In addition, the clinical possibilities for SMANCS are discussed, including the suggestion that angiotensin II-induced hypertension has clinical potential in improving the selective delivery of macromolecular drugs (i.e. SMANCS) to tumors. Aqueous SMANCS formulations have been tested in pilot studies in patients with solid tumors of the ovary, esophagus, lung, stomach, adrenal gland and in the brain. Formulations based on SMANCS/Lipiodol have been shown to be effective both as a diagnostic tool and for therapeutic use in solid tumors where the formulations are given arterially via a catheter. In a pilot study in primary unresectable hepatoma, an objective reduction in tumor size was observed for about 90% of cases when an adequate amount of the macromolecular drug was administered. A patient receiving such treatment with no active liver cirrhosis and tumor nodules/lesion confined within one liver segment might expect to have a 90% chance of survival after treatment for at least 5 years.

Styrene maleic acid neocarzinostatin treatment for hepatocellular carcinoma.

A variety of treatments have recently been introduced to improve the prognosis of hepatocellular carcinoma (HCC). These anticancer therapies include the oily carcinostatic agent styrene maleic acid neocarzinostatin (SMANCS). SMANCS is a chemical conjugate of a synthetic copolymer of styrene maleic acid (SMA) and the proteinaceous anti-cancer agent neocarzinostatin (NCS), which dissolves in organic solvents such as pyridine and acetone, and particularly in Lipiodol. NCS is a simple protein capable of inhibiting DNA synthesis and inducing DNA degradation. Lipiodol is an ethyl ester of iodinated poppy seed oil in which most of the unsaturated double bonds in oleic, linoleic and linolenic acid are almost completely iodinated. When a homogeneous suspension of SMANCS with Lipiodol (SMANCS/Lipiodol) is administered intra-arterially, Lipiodol acts as a carrier of SMANCS. Many studies have demonstrated the clinical efficacy of SMANCS/Lipiodol in the treatment of HCC. We have shown that transcatheter arterial infusion (TAI) with SMANCS/Lipiodol has a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of HCC. However, recent clinical studies have indicated that SMANCS causes severe adverse reactions and complications. We have also reported a case of HCC in which multifocal hepatic infarction developed after TAI with SMANCS/Lipiodol. Arterial administration of SMANCS/Lipiodol, therefore, should be given as peripherally as possible via the tumor feeding arteries, to enhance the efficacy of the agent and to reduce the adverse effects.

Antitumour activity of an immunoconjugate composed of anti-human astrocytoma monoclonal antibody and neocarzinostatin.

Neocarzinostatin (NCS) linked to the thiol group on the hinge region of the Fab' fragment of GA-17, a murine monoclonal antibody reacting with tyrosine-specific phosphorylated antigens, which are exclusively expressed on the cell surface of human astrocytomas, was evaluated for in vivo activity. GA-17-NCS immunoconjugates significantly suppressed the growth of human malignant glioma cell line U87-MG subcutaneous xenografts in nude mice until day 50 when administered intravenously into the tail vein. Disulphide- and thioether-linked GA-17-NCS were nearly equipotent immunoconjugates, but thioether-linked GA-17-NCS was more effective than disulphide-linked conjugates with 250 U/kg NCS content on day 50 (P < 0.05). Thioether-linked GA-17-NCS was significantly more effective on day 50 than free NCS with 500 U/kg or 250 U/kg NCS content (P < 0.05, P < 0.01, respectively). These results suggest that GA-17-NCS may prove useful in the treatment of human malignant gliomas.

The design of cytotoxic-agent-antibody conjugates.

The rationale for the use of antibodies as carriers of cancer chemotherapeutic agents is based upon: the presence on cells of tumor-associated cell surface antigens (TAA); the ability to obtain specific polyclonal or monoclonal antibodies against them; and the availability of methods for binding appropriate toxic agents or radionuclides with retention of activity of both antibody and agents. The general finding so far has been that both conventional polyclonal and hybridoma-derived monoclonal antibodies can deliver cytocidal amounts of toxic agents to target tumor cells both in vitro and in vivo. Moreover, various agents with different modes of antitumor activity (e.g., DNA intercalation or alkylation, enzyme inhibition, and cell surface modification) have all produced superior tumor inhibition in conjugate form compared to the individual or synergistic inhibition produced by agent and antibody. Recent studies are contributing to the understanding of the mechanism of action of drug-antibody conjugates and are thus establishing guidelines for this approach to cancer therapy.

Targeted chemotherapy in mice with peritoneally disseminated gastric cancer using monoclonal antibody-drug conjugate.

The murine monoclonal antibody A7 (MAb A7) is reactive against most human gastric cancer cell lines. Using a nude mouse peritoneal dissemination model of human gastric cancer, we investigated targeted chemotherapy using a conjugate of neocarzinostatin (NCS) with MAb A7 (A7-NCS). After demonstrating cytotoxicity of the complex against the human gastric cancer cell line MKN45 in vitro, we intraperitoneally injected A7-NCS, NCS or saline into nude mice bearing peritoneally disseminated human gastric cancer. A7-NCS inhibited peritoneal dissemination significantly more effectively than NCS. MAb A7 may prove to be an effective carrier for antineoplastic drugs in patients with peritoneal dissemination of gastric cancer.

A novel dosage approach for evaluation of SMANCS [poly-(styrene-co-maleyl-half-n-butylate) - neocarzinostatin] in the treatment of primary hepatocellular carcinoma.

We report a Phase I/II clinical trial of poly-(styrene-co-maleyl-half-n-butylate)-neocarzinostatin (SMANCS) for intra-arterial treatment of hepatoma. Early patients received 4 or 8 mg SMANCS dissolved in Lipiodol; later patients were treated according to tumour size and degree of filling achieved. SMANCS/Lipiodol drained rapidly from normal liver but was retained within tumour interstitium. Tumour nodules filled with SMANCS/Lipiodol usually stabilised and often regressed. No UICC criteria-defined responses were achieved, partly due to difficulties of filling several lesions simultaneously. Signs of therapeutic activity suggest a more extensive clinical study is warranted.

Tumor-targeted chemotherapy with lipid contrast medium and macromolecular anticancer drug (SMANCS) for renal cell carcinoma.

Twenty-five patients with renal cell carcinoma were treated with a lipophilic macromolecular drug, poly(stylene-co-maleic acid)-conjugated neocarzinostatin (SMANCS) dissolved in lipid contrast medium (Lipiodol). The drug was injected by catheterizing the renal artery and another feeding artery in 24 patients, and in the common hepatic artery in 1 patient with metastases to the liver after a radical nephrectomy. The procedure of selective arterial administration of 3-20 mg/mL of SMANCS/Lipiodol was simple to perform and was required once every two to three weeks. Total dose of SMANCS for each patient varied from 3 to 57 mg. Both SMANCS and Lipiodol accumulated more selectively in tumor than in any other tissue and remained in the neovasculature and extracapillary space for a long time. CT pattern of the remaining oil contrast medium in the tumor was characterized by the high-density area localized mainly in the periphery of the tumor around the central necrosis. When hyperviscosity Lipiodol (Lipiodol HV) was used as lipid contrast medium, it remained more persistently in the tumor and disappeared more slowly than Lipiodol. Moreover, the pronounced anticancer effect was recognized when SMANCS/Lipiodol HV was administered compared with only SMANCS/Lipiodol. Severe side effects, such as myelosuppression, unendurable pain, paralytic ileus, etc., were not observed. This targeting chemotherapy may be of great significance for advanced renal cell carcinoma.

A pharmacokinetic simulation model for chemotherapy of brain tumor with an antitumor protein antibiotic, neocarzinostatin. Theoretical considerations behind a two-compartment model for continuous infusion via an internal carotid artery.

A pharmacokinetic two-compartment model for the treatment of brain tumors in man was simulated with the aid of a computer. The parameters necessary for the simulations such as inactivation rate constant, elimination rate constant, distribution volume, blood volume, cerebral blood flow, and cytotoxic drug concentration were either determined in this study or obtained from the literature. A proteinaceous antitumor antibiotic, neocarzinostatin (NCS), was utilized as a prototype drug because it has features making it advantageous in the treatment of brain tumor. In particular, NCS has an extremely short half-life in serum (t 1/2 less than or equal to 3 s), while it is relatively stable in the cerebrospinal fluid (CSF) (t 1/2 approximately 50 s). Therefore, the drug level in the cerebral compartment can be made adequately high with an appropriate infusion velocity into the cerebral compartment; however, it was possible to keep the plasma level of the drug much lower than the toxic level. Thus, few side-effects should result. In an in vitro study, NCS was found to exhibit its cytotoxicity to glioblastoma cells at a concentration as low as 0.005 microgram/ml. In contrast, the cytotoxicity was not apparent for the normal glia cells at 0.1 microgram/ml. The model being considered in this investigation is a two-compartment model, which consists of the cerebral compartment and the rest of the circulatory system of the body. In this case the drug is infused via an internal carotid artery. The results of pharmacokinetic simulation and dose regimens for NCs are presented, based on the effective concentration of the drug to glioblastoma cells in culture and the available pharmacological parameters.

Clinical pharmacology of the anticancer polypeptide neocarzinostatin.

The clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400-3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7 h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3 l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearance, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1-5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.