zinostatin and Colorectal-Neoplasms

Application of monoclonal antibody for diagnosis and therapy of colorectal cancer was reviewed. The history and present status of radioimmunoimaging of cancer were presented. Immuno-guided surgery using radiolabeled antibody and hand-aided detector during surgery is a promising approach for complete excision of cancerous region. Also, a new antibody labeling method using a micro-magnet instead of radioisotopes may lead to a new era in immunodiagnosis of cancer. Finally, immunotargeting chemotherapy using antibody-anticancer drug conjugates was reviewed. A new type of immunoconjugate composed of human/mouse chimeric antibody and Neocarzinostatin seems to be one of the most promising drug formulas for immunotargeting chemotherapy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Colorectal Neoplasms; Humans; Immunotoxins; Radioimmunodetection; Zinostatin

In this review, the rationale of regional chemotherapy for treatment of hepatic metastases in advanced colorectal carcinoma is discussed. Pharmacokinetic principles and early clinical experience of hepatic arterial drug administration are summarised. The regional advantage of fluoropyrimidine compounds in this setting is well established, and recent evidence suggests that 5-fluorouracil (5-FU) is more efficacious than the analogue 5-fluoro-2'-deoxyuridine (FUDR). However, while significantly higher clinical response rates can be achieved with hepatic arterial infusion (HAI) chemotherapy compared with conventional intravenous drug administration, patient survival benefit is not significantly different. Several novel approaches to overcome the limitations of HAI therapy are currently being explored. These include concomitant use of biodegradable microspheres, which both slow tumour blood flow and enhance tumour drug uptake, and use of vasoactive agents to redistribute arterial blood flow towards tumours. In addition, novel chemotherapeutic agents which exploit unique biological characteristics of hepatic tumours are entering clinical trial.

Topics: Colorectal Neoplasms; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Maleic Anhydrides; Mitomycin; Polystyrenes; Zinostatin

Liver metastases are the major cause of death for patients with colorectal cancer. Surgical resection is at present the only curative option. Styrene maleic acid neocarzinostatin [SMANCS/Lipiodol (S/L)] targets the unique vascular architecture of tumor blood vessels, which are hyperpermeable and lack a well-developed lymphatic system. Here we report changes in the microvascular architecture of liver metastases by scanning electron microscopy (SEM) following the administration of S/L.. Liver metastases were induced by the intrasplenic injection of dimethylhydrazine induced colon cancer cells in mice. In this model tumor angiogenesis occurs at day 10, while exponential tumor growth occurs at day 16. Changes in the tumor microvasculature were observed at 3 weeks following treatment with S/L at these time points by SEM of corrosion casts.. Tumors treated with S/L at day 10 appear similar to day 10 controls. Tumor vessels, 50 +/- 18 microm in diameter, are easily identified from hepatic vessels. Within the hepatic sinusoids are avascular spaces, 144 +/- 60 microm in diameter, which correspond to tumor cell aggregates at the initial stages of growth. Similarly, day 16 treated tumors appear comparable to day 16 controls. These vessels are narrower (84 +/- 32 microm vs. 150 +/- 70 microm) than their control counterparts. This is in contrast to vessels (216 +/- 36 microm in diameter) of a complex nature at 3 weeks.. S/L exerts a marked and immediate effect on the tumor microvessels at both the angiogenic and the exponential phases of tumor growth. This agent is effective at the microvascular level during inhibition of metastatic growth.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Contrast Media; Corrosion Casting; Iodized Oil; Liver Circulation; Liver Neoplasms, Experimental; Male; Maleic Anhydrides; Mice; Mice, Inbred CBA; Microcirculation; Microscopy, Electron, Scanning; Necrosis; Neovascularization, Pathologic; Polystyrenes; Zinostatin

The anticancer polypeptide neocarzinostatin (NCS) was covalently coupled to a human/mouse chimeric Fab A7 monoclonal antibody (chFabA7) and the in vivo efficacy of this conjugate was examined. NCS concentration assay was carried out, and acute toxicity and tumoricidal effects were examined. The concentration assay, using anti-NCS monoclonal antibody, revealed that administration of the chA7Fab conjugate leads to a greater blood retention and a higher tumor accumulation of NCS, when compared to free NCS administration. The tumoricidal effect of chA7Fab-NCS was higher than that of either free NCS or the saline control, against antigen-positive tumors. In antigen-negative tumors there was no difference in toxic effect among the three preparations. Values of LD50, reflecting acute toxicity, were 5050 U/kg and 3600 U/kg for the chA7Fab-NCS and the free NCS, respectively. These results suggest that chFabA7-NCS may be a promising tool for targeting cancer chemotherapy.

Topics: Animals; Antibodies, Monoclonal; Colorectal Neoplasms; Humans; Immunotoxins; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Recombinant Fusion Proteins; Zinostatin

Immunoconjugates composed of mouse monoclonal antibody and anticancer drug was applied for the treatment of patients with colorectal cancer. Administration of mouse antibody raised human anti-mouse antibody that may interfere with the effect of immunoconjugates. To resolve this problem, human/mouse chimeric antibody was prepared and immunoconjugate of chimeric antibody and anticancer drug was developed. The characteristics of this new immunoconjugate were described.

Topics: Animals; Antibodies, Monoclonal; Colorectal Neoplasms; Humans; Immunotoxins; Mice; Zinostatin

To examine whether or not immunoconjugate-A7-NCS can contribute for the reduction of local recurrence of colorectal cancer, the present study was undertaken. The study included examination of local retension, lymphatic delivery and inhibitory effect on tumor development after local administration of A7-NCS. The result showed that locally injected A7-NCS showed a high local retension, a high regional lymph node accumulation and a high inhibitory effect on tumor development. This finding indicates that A7-NCS can be a new promising tool for reducing the local recurrence of colorectal cancer.

Topics: Animals; Antibodies, Monoclonal; Colorectal Neoplasms; Immunotoxins; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm Transplantation; Zinostatin

A total of 77 patients with advanced colorectal cancer, including postoperative patients with liver, lung and peritoneal metastases, were treated with single or multiple injections of monoclonal antibody A7-neocarzinostatin (A7-NCS). A follow-up study of the patients treated with A7-NCS was done and the clinical outcome was compared with that of patients given other chemotherapies. In the postoperative patients with liver metastasis, the A7-NCS treatment prolonged survival time when compared with systemic administration of anticancer drugs, while it showed a similar survival time to chemoembolization using multiple anticancer agents suspended in a lipid contrast medium. Among the patients who underwent surgical resection of primary cancer, with or without liver metastasis, there was no difference in overall 5-year survival rate between the group treated with A7-NCS and the group treated with the other chemotherapies. However, the survival time of the patients treated with A7-NCS was longer than that of the patients treated with the other chemotherapies. In addition, the patients given a higher dose of A7-NCS had a longer survival time than the patients given a lower dose of A7-NCS. Human anti-mouse antibody was detected in all the A7-NCS-treated patients examined. There were no serious side effects in any of the patients given A7-NCS. Thus, this study indicates that the A7-NCS treatment is safe and useful for colorectal cancer patients, though some problems remain, such as optimization of injection dose, route, interval, etc., and overcoming human anti-mouse antibody development.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Immunoglobulin E; Immunoglobulin M; Immunotoxins; Liver Neoplasms; Male; Middle Aged; Mitomycin; Survival Rate; Zinostatin

Monoclonal antibody drug conjugate A7 was prepared from a mouse splenocyte immunized against human colon cancer. A7 reacted with 80 percent of colorectal cancer and pancreatic cancer. A7 was bound covalently to neocarzinostatin (NCS) to form A7-NCS. A7-NCS had strong cytotoxic activity in vivo and in vitro study. A total of 77 patients with colorectal cancer, including the patients with liver, lung and peritoneal metastasis, were treated with A7-NCS. There were some tumor reduction of liver metastasis on CT scan and pain relief. Follow up study of colorectal cancer patients treated with monoclonal antibody drug conjugate A7-NCS was carried out, with comparing to those treated conventional chemotherapy. Survival rate of the patients with postoperative liver metastasis treated with A7-NCS was slightly higher than that of the patients treated with conventional intraarterial infusion chemotherapy. There was no difference between the group treated with A7-NCS and that treated with conventional chemotherapy in the overall postoperative survival. Patients given a higher dose of the conjugate had a higher survival rate. There were no serious adverse effects in the patients given A7-NCS. Human anti-mouse antibody (HAMA) was detected in all A7-NCS treated patients.

Topics: Antibodies, Monoclonal; Colorectal Neoplasms; Combined Modality Therapy; Follow-Up Studies; Humans; Neoplasm Metastasis; Survival Rate; Zinostatin

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.

Topics: Animals; Antibodies, Monoclonal; Colorectal Neoplasms; Humans; Immunotoxins; Injections, Intralesional; Injections, Intravenous; Iodine Radioisotopes; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm Transplantation; Tissue Distribution; Tumor Cells, Cultured; Zinostatin

Monoclonal antibody-drug conjugate, A7-NCS, was applied for 73 patients with colorectal and pancreatic cancer, including metastasis of liver, lung and peritoneum. Monoclonal antibody A7, from a mouse splenocyte immunized against human colon cancer was bound covalently to Neocarzinostatin (NCS), Mitomycin C (MMC) and Adriamycin (ADM) to form A7-NCS, A7-MMC and A7-ADM, respectively. Fifty-four patients with colon cancer, fifteen patients with postoperative liver metastasis of colorectal cancer and one patient with advanced pancreatic cancer were given A7-NCS intra-arterially. Two patients with postoperative lung metastasis of colon cancer were injected intra-venously and one patient with postoperative peritoneal metastasis of colon cancer was given it intraperitoneally. Three patients with liver metastasis showed evidence of tumor reduction on CT scan and three claimed pain relief. Postoperative survival of the patients with distant metastasis exhibited slightly higher survival rate in the patients with A7-NCS, as compared with the patients without A7-NCS. There was no serious adverse effect in the patients given A7-NCS. Human anti-mouse antibody (HAMA) was detected in all patients given the conjugate. Repeated injections of A7-NCS for several consecutive days following the first injection brought about the same A7 pattern as the first injection.

Topics: Aged; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Colorectal Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Humans; Immunotoxins; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Pancreatic Neoplasms; Prognosis; Survival Rate; Zinostatin

This study was undertaken to evaluate the effectiveness of perioperative adjuvant chemotherapy for the treatment and prevention of lymph node metastasis of colorectal cancer. Namely, ten thousand unit (U) of NCS, the high molecular weight anti-tumor agent, was injected into the subserosa of the colon (n = 51), the tumor-feeding arteries (n = 6), or the peripheral veins (n = 6) immediately after laparotomy, and tissue concentration of NCS in the regional lymph nodes and intestinal wall was measured. After the injection of NCS into the subserosa, the regional lymph nodes showed higher concentration of 4.55-6.34U/g regardless of metastasis. Concentrations in the lymph nodes after NCS into the tumor-feeding arteries showed similar high level as those after the subserosal injection in Group 1 lymph nodes (paracolic and epicolic nodes), but not in Group 2 lymph nodes (intermediate nodes). The injection of NCS into the peripheral veins demonstrated a wide range of 0.01-5.0U/g, half of them being not effective concentrations. Perioperative injection of NCS into the subserosa in the colorectal cancer was technically simple and safe and a large amount of the agent was taken into the regional lymph nodes. Therefore, this strategy may be a rational treatment for slight or jumping metastases in the lymph nodes.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Colon; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Injections; Injections, Intra-Arterial; Injections, Intravenous; Intraoperative Care; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Serous Membrane; Tissue Distribution; Zinostatin