bryostatin-1 and Head-and-Neck-Neoplasms

Bryostatin-1 is a macrocyclic lactone that has been shown to modulate Protein Kinase C activity and has demonstrated antitumor activity in vitro and in vivo. Fifteen patients with metastatic or recurrent squamous cell carcinoma of the head and neck were treated with bryostatin-1 at a dose of 25 mcg/m2 by continuous intravenous infusion over 24 hours once weekly for three weeks followed by a break week to complete a four-week cycle. There were no major objective responses in the 14 evaluable patients. One patient with nasopharynx cancer had disease stabilization for 4 months prior to being removed from the study due to medical issues. This clinical benefit corresponded to a radiographic decrease in metabolic activity on positron emission tomograpy (PET) scan as well as molecular evidence of tumor apoptosis in a poly[ADP-ribose] polymerase (PARP) cleavage assay. Bryostatin-1 is not recommended for use as a single agent for the treatment of squamous cell head and neck cancer. Further investigation is warranted to determine the strength of the correlation between bryostatin-1 activity and PARP cleavage as a surrogate molecular marker of apoptosis.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Lactones; Macrolides; Male; Middle Aged; Neoplasm Recurrence, Local

Bryostatin 1 is a marine derived macrolactone with antineoplastic activity modulated through protein kinase C, and with good activity in in vitro and in vivo models. There are few drugs that offer palliation for metastatic soft-tissue sarcoma and head and neck cancer, and drugs with new mechanisms of action warrant detailed disease specific study.. Two phase II studies for patients with incurable soft tissue sarcoma (12), or head and neck cancer (12) were conducted. Patients were treated with bryostatin, 120 mg/m2/72 hours every 2 weeks for 3 cycles prior to re-evaluation. Most patients had received prior chemotherapy.. No patients had objective responses to therapy. Six patients had brief periods of disease stabilization. Toxicity was generally mild, with myalgia being prominent (n=8). Hyponatremia, not previously described, occurred in 5 patients. The mechanism of this toxicity was unclear.. Bryosytatin 1 given as a single agent for advanced adult soft tissue sarcoma and head and neck cancer is inactive. Myalgia and hyponatremia were the predominant toxicities.

Topics: Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Bryostatins; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Lactones; Macrolides; Male; Middle Aged; Sarcoma; Treatment Outcome

Protein kinase C (PKC) influences cellular sensitivity to cis-diamminedichloroplatinum(II) (cDDP). We have investigated whether the PKC signal transduction pathway is affected during the development of cellular resistance to cDDP. Activators of PKC, such as phorbol 12,13-dibutyrate (PDBu), enhanced the sensitivity of human small cell lung cancer H69 cells to cDDP by 2-fold but had no effect on the sensitivity of cDDP-resistant H69 cells (H69/CP) to cDDP. The maximum sensitization was achieved with 10 nM PDBu and blocked by down-regulation of PKC with higher concentrations of PDBu (1 microM) or bryostatin 1 (0.1 microM). PKC activity was decreased significantly in H69/CP cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cDDP. A modest decrease in PKC activity was also observed in etoposide-resistant H69 (H69/VP-16) cells but not in Taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells. H69 cells expressed conventional PKC alpha and-beta, novel PKC delta, atypical PKC zeta and-iota, and novel/atypical PKC mu. A decrease in cPKC alpha and-beta and an increase in nPKC delta were associated with the cDDP-resistant phenotype. The abundance of aPKC zeta or-iota was unaffected. H69/ VP-16 cells also displayed a reduction in cPKC beta and an increase in nPKC delta. Taxol-resistant H69 cells had no alteration in the expression of any of the PKC isozymes. Thus, a reduction in cPKCs and an increase in nPKC may be associated with cDDP resistance.

Topics: Antineoplastic Agents; Bleomycin; Bryostatins; Carcinoma; Carcinoma, Small Cell; Cisplatin; Drug Resistance, Neoplasm; Enzyme Activation; Etoposide; Female; Head and Neck Neoplasms; Herpes Simplex Virus Protein Vmw65; Humans; Lactones; Lung Neoplasms; Macrolides; Ovarian Neoplasms; Paclitaxel; Phorbol 12,13-Dibutyrate; Protein Kinase C; Signal Transduction; Tumor Cells, Cultured

Bryostatins are an important class of protein kinase C (PKC) activators. We have investigated the effect of bryostatin 1 on the antiproliferative activity of cis-diamminedichloroplatinum(II) (CP). A 24-h pretreatment of HeLa cells with 1 nM bryostatin 1 increased cellular sensitivity to CP by 4-fold. The effect of bryostatin 1 on the IC50 of CP (concentration of drug required to inhibit cell proliferation by 50%) was concentration-dependent and biphasic; the maximum effect of bryostatin 1 was seen with 1 nM, but higher concentrations of bryostatin 1 (greater than or equal to 10 nM) produced less CP sensitization. Although bryostatin 1 and phorbol esters caused an equivalent stimulation of HeLa cell PKC in cell-free systems, bryostatin 1 was less effective than phorbol esters in sensitizing cells to CP. Additionally, higher concentrations of bryostatin 1 (greater than or equal to 10 nM) antagonized CP sensitization by phorbol esters. Bryostatin 1 was even more potent than 12-O-tetradecanoylphorbol-13-acetate in inducing PKC down-regulation, and the maximum down-regulation was achieved with 10 nM bryostatin 1. Bryostatin 1 also increased cellular sensitivity to a CP analogue, cis-dichloro(ethylenediamine)platinum(II). A 24-h pretreatment with 1 nM bryostatin 1 increased cellular cis-[3H]DEP by 60%. The concentration- and time-dependent enhancement in CP sensitivity by bryostatin 1 was related to the increase in cis-[3H]DEP level. Thus, cellular accumulation of CP may be regulated by a PKC-dependent phosphorylation event.

Topics: Antineoplastic Agents; Biological Transport; Bryostatins; Cell Division; Cell Line; Cisplatin; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Head and Neck Neoplasms; HeLa Cells; Humans; Isoenzymes; Kinetics; Lactones; Macrolides; Organoplatinum Compounds; Phorbol 12,13-Dibutyrate; Protein Kinase C; Tetradecanoylphorbol Acetate; Time Factors