zinostatin and Carcinoma--Squamous-Cell

Topics: Animals; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Humans; Immunotoxins; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Zinostatin

Neocarzinostatin (NCS) was bound covalently to human/mouse chimeric Fab fragments of MAb A7 (chA7Fab) directed against human pancreatic carcinoma. The anti-tumour effect of chA7Fab-NCS was tested in a nude mouse model on pancreatic carcinoma and compared with A7-NCS or NCS alone. The anti-tumour effect of chA7Fab-NCS increased in a dose-dependent manner and was significantly greater than either A7-NCS or NCS. Tumour growth was completely suppressed after the administration of chA7Fab-NCS. An enzyme-linked immunosorbent assay with rabbit anti-mouse immunoglobulin was performed to examine the antigenicity of chA7Fab. ChA7Fab had less reactivity with rabbit anti-mouse immunoglobulin than either whole antibody A7 or murine Fab fragments of A7. Thus, chA7Fab-NCS can inhibit human pancreatic cancer growth in an animal and may be useful for targeting chemotherapy to pancreatic cancer in humans.

Topics: Animals; Antibodies, Anti-Idiotypic; Carcinoma, Squamous Cell; Humans; Immunotoxins; Mice; Mice, Nude; Neoplasms, Experimental; Pancreatic Neoplasms; Recombinant Fusion Proteins; Transplantation, Heterologous; Zinostatin

The murine monoclonal antibody (Mab) A7 conjugated to neocarzinostatin (A7-NCS) was injected intratumorally (IT) into tumor bearing nude mice. Its pharmacokinetics and tumoricidal effects were compared in the high, moderate and low antigen expressing xenograft for SW1116, WiDr and KB tumor-bearing nude mice, respectively. When injected IT into nude mice, [125I]A7-NCS was retained in the tumors according to the degree of antigen expression; it was also disseminated into the blood inverse proportion to the antigen expression. Addition of an excess amount of Mab A7 reduced [125I]-A7-NCS accumulation in SW1116 xenograft and elevated the [125I]A7-NCS concentration in the circulation. Complete tumor reduction was found in all 5 mice with SW1116 tumor, and 2 of 5 mice with WiDr tumor. However, only incomplete tumor suppression was observed in mice with the KB tumor. The significant tumor reduction in SW1116 bearing nude mice was attenuated when excess of Mab A7 was simultaneously administered with A7-NCS. These findings indicate that A7-NCS was localized in the target tumors and exerted its tumoricidal effects depending on the degree of antigen-antibody interaction when administered IT. Thus, A7-NCS can be used successfully in vivo for local therapy, auguring new and promising applications for local cancer therapy.

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Carcinoma, Squamous Cell; Colonic Neoplasms; Humans; Immunotoxins; Injections, Intralesional; Iodine Radioisotopes; KB Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Radioimmunoassay; Transplantation, Heterologous; Tumor Cells, Cultured; Zinostatin

The combined effect of radiation and YM-881 (SMANCS) was studied in vitro and in vivo. When 0.25 microgram/ml of YM-881 was simultaneously combined with radiation, during and after irradiation for 30 min in total, Dq decreased from 3.3 Gy to 1.4 Gy without changing D0 in the dose-survival curve of exponentially growing SCC VII tumor cells. Five or ten times administrations of 0.1 mg/kg YM-881 at an interval of 24 h did not inhibit tumor growth. However, administration of 0.1 mg/kg YM-881 just before every irradiation which was repeated five times at an interval of 24 h yielded dose modifying factors (DMFs) of 1.8-1.2 when the tumor response to treatment was evaluated by the time for the tumors to regrow to three times the original volume. Administration of YM-881 ten times just before every irradiation yielded DMFs of 1.3-1.2. Adverse effects of the combination on bone marrow were examined by spleen colony assay. After five injections of 0.1 mg/kg YM-881, the mean number of CFU-S per femur decreased to 77% of the pretreatment level, but this was not significant statistically (0.1 greater than p greater than 0.05). The slope of radiation response curve for CFU-S per femur was not affected by the combination.

Topics: Animals; Antibiotics, Antineoplastic; Bone Marrow; Carcinoma, Squamous Cell; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Furans; Male; Maleic Anhydrides; Mice; Neoplasms, Experimental; Polystyrenes; Tumor Cells, Cultured; Zinostatin

Twenty-four patients with various solid tumors including metastatic liver cancer and cancer of the lung, gallbladder, and pancreas were treated with a lipophilic macromolecular drug, copoly(styrene-maleic acid) conjugated neocarzinostatin (SMANCS). The drug was dissolved in a lipid contrast medium Lipiodol and administered by catheterizing the respective feeding arteries under x-ray monitoring. The advantages of this therapy include: (1) selective deposition of Lipiodol with the anti-cancer drug in the target tumor, (2) a pronounced and long-lasting anti-cancer effect, (3) enhanced visualization of the tumor on x-ray examinations for a prolonged period which also facilitated the long-term follow-up, (4) semiquantitative evaluation of the dosage regimen by x-ray examination before further administration, (5) general applicability due to procedural simplicity, and (6) little side effect. Since the amount of Lipiodol and SMANCS used per administration for a patient (1.0-5.0 ml; 1.0-5.0 mg) was far less than the anticipated toxicity (LD50 of Lipiodol = 95 ml/60 kg, dog, intravenously; and that of SMANCS = 3.4 mg/kg, mouse, IV), no deleterious effects to such critical organs as the brain, heart, lung, liver, or kidneys were observed upon radiologic and general clinical examination.

Topics: Adenocarcinoma; Aged; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Contrast Media; Female; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; Zinostatin