bryostatin-1 and Colorectal-Neoplasms

Current chemotherapy for patients with advanced colorectal cancer is relatively ineffective and may be associated with significant toxicity. Bryostatin 1 (bryo 1) influences cell proliferation, intracellular metabolism and signaling, differentiation, and apoptosis in human cancer cell lines via modulation of protein kinase C (PKC) activity. This trial investigates the efficacy and toxicity of bryo 1 as a novel therapeutic agent for patients with advanced colorectal cancer who have had previous 5-fluorouracil therapy. The primary end point was tumor response to bryo 1. Toxicity was also assessed. Twenty-eight patients with advanced colorectal cancer were enrolled. The mean age was 59 years (range, 38-76), with 16 men and 12 women, and good minority representation (11 African-Americans). The first 10 patients initially received 25 microg/m2 of bryo 1 weekly as a 24-h infusion for 3 weeks of every 4-week cycle, with dose escalation to 35 microg/m2 starting with the second cycle. The remaining patients were started at 35 microg/m2 and escalated to 40 microg/m2, if toxicity was minimal. Twenty-five patients were evaluable for objective tumor response, and complete data on toxicity were collected on 26 patients. No partial or complete tumor responses were observed. All 25 patients had disease progression within four cycles. Myalgia was the most common toxicity. Myelosuppression was not seen. bryo 1 as a weekly 24-h continuous infusion lacks single-agent antitumor activity in advanced colorectal cancer. Toxicity differs from that of traditional chemotherapeutic drugs.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Colorectal Neoplasms; Female; Humans; Infusions, Intravenous; Lactones; Macrolides; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome

Accumulating evidence suggest that some infectious agents may interfere in the natural progression of neoplasia. This study examined the association between chronic infection with adult Syphacia muris parasites and 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats. In addition, the conceivable therapeutic effect of Bryostatin-1, a potent extract of the marine Bryozoan, Bugulane ritina, was investigated against this combined effect.DMH administration has induced aberrant crypt foci (ACF), surrogate biomarkers for colorectal carcinogenesis, while the S. muris infection combined with DMH has significantly increased the total numbers of ACF. Nonetheless, treatment with Bryostatin-1 after infection has significantly reduced the ACF numbers particularly larger ones. This inhibition was concomitant with significant inhibition in the immunohistochemical levels of the ki67, Caspase-3 and IgM levels in colorectal epithelium, as well as serum levels of IgM and IgG. Additionally, treatment with Bryostatin-1 after S. muris + DMH has modulated enzymatic antioxidative markers levels of superoxide dismutase and catalase as well as the non-enzymatic antioxidant markers levels of reduced glutathione, lipid peroxidation, nitric oxide and total antioxidant capacity. Further, treatment with Bryostatin-1 has down-regulated the mRNA expression levels of COX-2 and APC genes in colorectal mucosa. In conclusion, infection with S. muris during colorectal carcinogenesis has significantly modulated the oxidative stress markers in the colorectum, while treatment with Bryostatin-1 has exerted significant curative potential. A mechanism could be explained that Bryostatin-1 treatment has reduced oxidative stress markers activities along with affecting host to parasite immunity possibly leading to changes in the COX-2 and APC expression, retarding cellular proliferation and subsequently reducing the colorectal carcinogenesis events.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Bryostatins; Carcinogenesis; Colorectal Neoplasms; Disease Models, Animal; Gene Expression; Immunohistochemistry; Oxidative Stress; Oxyuriasis; Oxyuroidea; Rats; Treatment Outcome