Bryostatin-1: A Novel PKC Inhibitor in Clinical Development

Cancer Investigation

Volumn 21, Issue 6, 2003, Pages 924-936

  Kortmansky, Jeremy ^a   Schwartz, Gary K ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BRYOSTATIN 1; CISPLATIN; LACTONE DERIVATIVE; MACROCYCLIC COMPOUND; PACLITAXEL; PROTEIN KINASE C INHIBITOR; VINCRISTINE;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BLEEDING; BRADYCARDIA; CANCER COMBINATION CHEMOTHERAPY; CELL DIFFERENTIATION; CELL PROLIFERATION; CELLULITIS; CHEMOTHERAPY INDUCED EMESIS; CLINICAL TRIAL; CONSTIPATION; DIARRHEA; DOWN REGULATION; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG EXPOSURE; DRUG HYPERSENSITIVITY; DRUG MECHANISM; DRUG POTENCY; DRUG SCREENING; DYSPNEA; EYE PAIN; FATIGUE; FEVER; FLUSHING; HEADACHE; HEMATOLOGIC MALIGNANCY; HUMAN; HYPOTENSION; INVERTEBRATE; LEUKOPENIA; LIVER TOXICITY; MYALGIA; NAUSEA; NEUTROPENIA; PHOTOPHOBIA; PRIORITY JOURNAL; RASH; REVIEW; SIDE EFFECT; SOLID TUMOR; SUPRAVENTRICULAR TACHYCARDIA; THROMBOCYTOPENIA; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL DIFFERENTIATION; CLINICAL TRIALS, PHASE I; CLINICAL TRIALS, PHASE II; DOWN-REGULATION; HUMANS; LACTONES; MACROLIDES; NAUSEA; PAIN; PROTEIN KINASE C; VOMITING;

EID: 0346096818     PISSN: 07357907     EISSN: None     Source Type: Journal    
DOI: 10.1081/CNV-120025095     Document Type: Review

References (119)

1. Jarvis, W.D.; Grant, S. Protein kinase C targeting in antineoplastic treatment strategies. Invest. New Drugs 1999, 17, 227-240.
2. Mellor, H.P.P. The extended protein kinase C superfamily. Biochem. J. 1998, 332, 281-292.
3. Cartee, L.; Davis, C.; Lin, P.S.; Grant, S. Chronic exposure to bryostatin-1 increases the radiosensitivity of U937 leukaemia cells ectopically expressing Bcl-2 through a non-apoptotic mechanism. Int. J. Radiat. Biol. 2000, 76, 1323-1333.
4. Mutter, R.; Wills, M. Chemistry and clinical biology of the bryostatin-1s. Bioorg. Med. Chem. 2000, 8, 1841-1860.
5. Wender, P.A.; Cribbs, C.M.; Koehler, K.F.; Sharkey, N.A.; Herald, C.L.; Kamano, Y.; Pettit, G.R.; Blumberg, P.M. Modeling of the bryostatin-1s to the phorbol ester pharmacophore on protein kinase C. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 7197-7201.
6. Kraft, A.S.; Smith, J.B.; Berkow, R.L. Bryostatin-1, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl. Acad. Sci. U. S. A. 1986, 83, 1334-1338.
7. de Vries, D.J.; Herald, C.L.; Pettit, G.R.; Blumberg, P.M. Demonstration of sub nanomolar affinity of bryostatin-1 for the phorbol ester receptor in rat brain. Biochem. Pharmacol. 1988, 37, 4069-4073.
8. Hennings, H.; Blumberg, P.M.; Pettit, G.R.; Herald, C.L.; Shores, R.; Yuspa, S.H. Bryostatin-1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 1987, 8, 1343-1346.
9. Isakov, N.; Galron, D.; Mustelin, T.; Pettit, G.R.; Altman, A. Inhibition of phorbol ester-induced T cell proliferation by bryostatin-1 is associated with rapid degradation of protein kinase C. J. Immunol. 1993, 150, 1195-1204.
10. Lee, H.W.; Smith, L.; Pettit, G.R.; Vinitsky, A.; Smith, J.B. Ubiquitination of protein kinase C-alpha and degradation by the proteasome. J. Biol. Chem. 1996, 271, 20973-20976.
11. Hu, Z.B.; Ma, W.; Uphoff, C.C.; Lanotte, M.; Drexler, H.G. Modulation of gene expression in the acute promyelocytic leukemia cell line NB4. Leukemia 1993, 7, 1817-1823.
12. Song, X.; Sheppard, H.M.; Norman, A.W.; Liu, X. Mitogen-activated protein kinase is involved in the degradation of p53 protein in the bryostatin-1-induced differentiation of the acute promyelocytic leukemia NB4 cell line. J. Biol. Chem. 1999, 274, 1677-1682.
13. al-Katib, A.; Mohammad, R.M.; Khan, K.; Dan, M.E.; Pettit, G.R.; Sensenbrenner, L.L. Bryostatin-1-induced modulation of the acute lymphoblastic leukemia cell line Reh. J. Immunother. 1993, 14, 33-42.
14. Lilly, M.; Tompkins, C.; Brown, C.; Pettit, G.; Kraft, A. Differentiation and growth modulation of chronic myelogenous leukemia cells by bryostatin-1. Cancer Res. 1990, 50, 5520-5525.
15. Li, Y.; Mohammad, R.M.; al-Katib, A.; Varterasian, M.L.; Chen, B. Bryostatin-1 (bryo1)-induced monocytic differentiation in THP-1 human leukemia cells is associated with enhanced c-fyn tyrosine kinase and M-CSF receptors. Leuk. Res. 1997, 21, 391-397.
16. Hu, Z.B.; Ma, W.; Uphoff, C.C.; Quentmeier, H.; Drexler, H.G. C-kit expression in human megakaryoblastic leukemia cell lines. Blood 1994, 83, 2133-2444.
17. Mohammad, R.M.; Maki, A.; Pettit, G.R.; al-Katib, A.M. Bryostatin-1 induces ubiquitin COOH-terminal hydrolase in acute lymphoblastic leukemia cells. Enzyme Protein 1996, 49, 262-272.
18. al-Katib, A.; Mohammad, R.M.; Dan, M.; Hussein, M.E.; Akhtar, A.; Pettit, G.R.; Sensenbrenner, L.L. Bryostatin-1-induced hairy cell features on chronic lymphocytic leukemia cells in vitro. Exp. Hematol. 1993, 21, 61-65.
19. al-Katib, A.; Mohammad, R.M.; Mohamed, A.N.; Pettit, G.R.; Sensenbrenner, L.L. Conversion of high grade lymphoma tumor cell line to intermediate grade with TPA and bryostatin-1 as determined by polypeptide analysis on 2D gel electrophoresis. Hematol. Oncol. 1990, 8, 81-89.
20. Mohammad, R.M.; Hamdan, M.Y.; al-Katib, A. Induced expression of alpha-enolase in differentiated diffuse large cell lymphoma. Enzyme Protein 1994, 48, 37-44.
21. Hocevar, B.A.; Fields, A.P. Selective translocation of beta II-protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells. J. Biol. Chem. 1991, 266, 28-33.
22. Fields, A.P.; Pettit, G.R.; May, W.S. Phosphorylation of lamin B at the nuclear membrane by activated protein kinase C. J. Biol. Chem. 1988, 263, 8253-8260.
23. Kraft, A.S.; Baker, V.V.; May, W.S. Bryostatin-1 induces changes in protein kinase C location and activity without altering c-myc gene expression in human promyelocytic leukemia cells (HL-60). Oncogene 1987, 1, 111-118.
24. Drexler, H.G.; Gignac, S.M.; Jones, R.A.; Scott, C.S.; Pettit, G.R.; Hoffbrand, A.V. Bryostatin-1 induces differentiation of B-chronic lymphocytic leukemia cells. Blood 1989, 74, 1747-1757.
25. May, W.S.; Tyler, P.G.; Ito, T.; Armstrong, D.K.; Qatsha, K.A.; Davidson, N.E. Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis. J. Biol. Chem. 1994, 269, 26865-26870.
26. Ruvolo, P.P.; Deng, X.; Carr, B.K.; May, W.S. A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J. Biol. Chem. 1998, 273, 25436-25442.
27. Kitada, S.; Zapata, J.M.; Andreeff, M.; Reed, J.C. Bryostatin-1 and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br. J. Haematol. 1999, 106, 995-1004.
28. Wall, N.R.; Mohammad, R.M.; Reddy, K.B.; Al-Katib, A.M. Bryostatin-1 induces ubiquitination and proteasome degradation of Bcl-2 in the human acute lymphoblastic leukemia cell line Reh. Int. J. Mol. Med. 2000, 5, 165-171.
29. Vrana, J.A.; Wang, Z.; Rao, A.S.; Tang, L.; Chen, J.H.; Kramer, L.B.; Grant, S. Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937): interactions with the macrocyclic lactone bryostatin-1. Leukemia 1999, 13, 1046-1055.
30. Mohammad, R.M.; Diwakaran, H.; Maki, A.; Emara, M.A.; Pettit, G.R.; Redman, B.; al-Katib, A. Bryostatin-1 induces apoptosis and augments inhibitory effects of vincristine in human diffuse large cell lymphoma. Leuk. Res. 1995, 19, 667-673.
31. Wang, H.; Mohammad, R.M.; Werdell, J.; Shekhar, P.V. p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin-1 in a highly metastatic mammary epithelial cell line: in vitro versus in vivo activity. Int. J. Mol. Med. 1998, 1, 915-923.
32. Wang, S.; Wang, Z.; Boise, L.H.; Dent, P.; Grant, S. Bryostatin-1 enhances paclitaxel-induced mitochondrial dysfunction and apoptosis in human leukemia cells (U937) ectopically expressing Bcl-xL. Leukemia 1999, 13, 1564-1573.
33. Wang, S.; Guo, C.Y.; Castillo, A.; Dent, P.; Grant, S. Effect of bryostatin-1 on taxol-induced apoptosis and cytotoxicity in human leukemia cells (U937). Biochem. Pharmacol. 1998, 56, 635-644.
34. Gschwend, J.E.; Fair, W.R.; Powell, C.T. Bryostatin-1 induces prolonged activation of extracellular regulated protein kinases in and apoptosis of LNCaP human prostate cancer cells overexpressing protein kinase calpha. Mol. Pharmacol. 2000, 57, 1224-1234.
35. Gomez-Angelats, M.; Bortner, C.D.; Cidlowski, J.A. Protein kinase C (PKC) inhibits fas receptor-induced apoptosis through modulation of the loss of K+ and cell shrinkage. A role for PKC upstream of caspases. J. Biol. Chem. 2000, 275, 19609-19619.
36. Basu, A.; Akkaraju, G.R. Regulation of caspase activation and cis-diamminedichloroplatinum(II)-induced cell death by protein kinase C. Biochemistry 1999, 38, 4245-4251.
37. Haussermann, S.; Kittstein, W.; Rincke, G.; Johannes, F.J.; Marks, F.; Gschwendt, M. Proteolytic cleavage of protein kinase Cmu upon induction of apoptosis in U937 cells. FEBS Lett. 1999, 462, 442-446.
38. Wall, N.R.; Mohammad, R.M.; Nabha, S.M.; Pettit, G.R.; Al-Katib, A.M. Modulation of cIAP-1 by novel antitubulin agents when combined with bryostatin-1 results in increased apoptosis in the human early pre-B acute lymphoblastic leukemia cell line Reh. Biochem. Biophys. Res. Commun. 1999, 266, 76-80.
39. Asiedu, C.; Biggs, J.; Lilly, M.; Kraft, A.S. Inhibition of leukemic cell growth by the protein kinase C activator bryostatin-1 correlates with the dephosphorylation of cyclin-dependent kinase 2. Cancer Res. 1995, 55, 3716-3720.
40. Vrana, J.A.; Saunders, A.M.; Chellappan, S.P.; Grant, S. Divergent effects of bryostatin-1 and phorbol myristate acetate on cell cycle arrest and maturation in human myelomonocytic leukemia cells (U937). Differentiation 1998, 63, 33-42.
41. Vrana, J.A.; Kramer, L.B.; Saunders, A.M.; Zhang, X.F.; Dent, P.; Povirk, L.F.; Grant, S. Inhibition of protein kinase C activator-mediated induction of p21CIP1 and p27KIP1 by deoxycytidine analogs in human leukemia cells: relationship to apoptosis and differentiation. Biochem. Pharmacol. 1999, 58, 121-131.
42. Koutcher, J.A.; Motwani, M.; Zakian, K.L.; Li, X.K.; Matei, C.; Dyke, J.P.; Ballon, D.; Yoo, H.H.; Schwartz, G.K. The in vivo effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic entry, and blood flow. Clin. Cancer Res. 2000, 6, 1498-1507.
43. Johnson, M.D.; Torri, J.A.; Lippman, M.E.; Dickson, R.B. Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness. Exp. Cell Res. 1999, 247, 105-113.
44. Wojtowicz-Praga, S.M.; Dickson, R.B.; Hawkins, M.J. Matrix metalloproteinase inhibitors. Invest. New Drugs 1997, 15, 61-75.
45. Al-Katib, A.M.; Smith, M.R.; Kamanda, W.S.; Pettit, G.R.; Hamdan, M.; Mohamed, A.N.; Chelladurai, B.; Mohammad, R.M. Bryostatin-1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res. 1998, 4, 1305-1314.
46. Scala, S.; Dickstein, B.; Regis, J.; Szallasi, Z.; Blumberg, P.M.; Bates, S.E. Bryostatin-1 affects P-glycoprotein phosphorylation but not function in multidrug-resistant human breast cancer cells. Clin. Cancer Res. 1995, 1, 1581-1587.
47. Puente, L.G.S.J.; Ostergaard, H.L. Evidence for protein kinase C-dependent and -independent activation of mitogen-activated protein kinase in T cells: potential role of additional diacylglycerol binding proteins. J. Immunol. 2000, 165, 6865-6871.
48. Kos, F.J.; Cornell, D.L.; Lipke, A.B.; Graham, L.J.; Bear, H.D. Protective role of IL-2 during activation of T cells with bryostatin-1. Int. J. Immunopharmacol. 2000, 22, 645-652.
49. Trenn, G.; Pettit, G.R.; Takayama, H.; Hu-Li, J.; Sitkovsky, M.V. Immunomodulating properties of a novel series of protein kinase C activators. The bryostatin-1s. J. Immunol. 1988, 140, 433-439.
50. Bosco, M.C.; Rottschafer, S.; Taylor, L.S.; Ortaldo, J.R.; Longo, D.L.; Espinoza-Delgado, I. The antineoplastic agent bryostatin-1 induces proinflammatory cytokine production in human monocytes: synergy with interleukin-2 and modulation of interleukin-2Rgamma chain expression. Blood 1997, 89, 3402-3411.
51. Lilly, M.; Brown, C.; Pettit, G.; Kraft, A. Bryostatin-1: a potential anti-leukemic agent for chronic myelomonocytic leukemia. Leukemia 1991, 5, 283-287.
52. Berkow, R.L.; Schlabach, L.; Dodson, R.; Benjamin, W.H. Jr.; Pettit, G.R.; Rustagi, P.; Kraft, A.S. In vivo administration of the anticancer agent bryostatin-1 activates platelets and neutrophils and modulates protein kinase C activity. Cancer Res. 1993, 53, 2810-2815.
53. Szallasi, Z.; Du, L.; Levine, R.; Lewin, N.E.; Nguyen, P.N.; Williams, M.D.; Pettit, G.R.; Blumberg, P.M. The bryostatin-1s inhibit growth of B16/F10 melanoma cells in vitro through a protein kinase C-independent mechanism: dissociation of activities using 26-epi-bryostatin-1. Cancer Res. 1996, 56, 2105-2111.
54. Schuchter, L.M.; Esa, A.H.; May, S.; Laulis, M.K.; Pettit, G.R.; Hess, A.D. Successful treatment of murine melanoma with bryostatin-1. Cancer Res. 1991, 51, 682-687.
55. Hornung, R.L.; Pearson, J.W.; Beckwith, M.; Longo, D.L. Preclinical evaluation of bryostatin-1 as an anticancer agent against several murine tumor cell lines: in vitro versus in vivo activity. Cancer Res. 1992, 52, 101-107.
56. Stanwell, C.; Gescher, A.; Bradshaw, T.D.; Pettit, G.R. The role of protein kinase C isoenzymes in the growth inhibition caused by bryostatin-1 in human A549 lung and MCF-7 breast carcinoma cells. Int. J. Cancer. 1994, 56, 585-592.
57. Hess, A.D.; Silanskis, M.K.; Esa, A.H.; Pettit, G.R.; May, W.S. Activation of human T lymphocytes by bryostatin-1. J. Immunol. 1988, 141, 3263-3269.
58. Kennedy, M.J.; Prestigiacomo, L.J.; Tyler, G.; May, W.S.; Davidson, N.E. Differential effects of bryostatin-1 and phorbol ester on human breast cancer cell lines. Cancer Res. 1992, 52, 1278-1283.
59. Dale, I.L.; Gescher, A. Effects of activators of protein kinase C, including bryostatin-1s 1 and 2, on the growth of A549 human lung carcinoma cells. Int. J. Cancer. 1989, 43, 158-163.
60. Mohammad, R.M.; Dugan, M.C.; Mohamed, A.N.; Almatchy, V.P.; Flake, T.M.; Dergham, S.T.; Shields, A.F.; Al-Katib, A.A.; Vaitkevicius, V.K.; Sarkar, F.H. Establishment of a human pancreatic tumor xenograft model: potential application for preclinical evaluation of novel therapeutic agents. Pancreas 1998, 16, 19-25.
61. Bodily, J.M.; Hoopes, D.J.; Roeder, B.L.; Gilbert, S.G.; Pettit, G.R.; Herald, C.L.; Rollins, D.N.; Robison, R.A. The inhibitory effects of bryostatin-1 administration on the growth of rabbit papillomas. Cancer Lett. 1999, 136, 67-74.
62. La Porta, C.A.; Di Dio, A.; Porro, D.; Comolli, R. Overexpression of novel protein kinase C delta in BL6 murine melanoma cells inhibits the proliferative capacity in vitro but enhances the metastatic potential in vivo. Melanoma Res. 2000, 10, 93-102.
63. McBain, J.A.; Pettit, G.R.; Mueller, G.C. Phorbol esters activate proteoglycan metabolism in human colon cancer cells en route to terminal differentiation. Cell Growth Differ. 1990, 1, 281-291.
64. Jones, R.J.; Sharkis, S.J.; Miller, C.B.; Rowinsky, E.K.; Burke, P.J.; May, W.S. Bryostatin-1, a unique biologic response modifier: anti-leukemic activity in vitro. Blood 1990, 75, 1319-1323.
65. Mohammad, R.M.; al-Katib, A.; Pettit, G.R.; Sensenbrenner, L.L. Successful treatment of human Waldenstrom's macroglobulinemia with combination biological and chemotherapy agents. Cancer Res. 1994, 54, 165-168.
66. McGown, A.T.; Jayson, G.; Pettit, G.R.; Haran, M.S.; Ward, T.H.; Crowther, D. Bryostatin-1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro. Br. J. Cancer. 1998, 77, 216-220.
67. Mohammad, R.M.; Varterasian, M.L.; Almatchy, V.P.; Hannoudi, G.N.; Pettit, G.R.; Al-Katib, A. Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin-1. Clin. Cancer Res. 1998, 4, 1337-1343.
68. Mohammad, R.M.; Wall, N.R.; Dutcher, J.A.; Al-Katib, A.M. The addition of bryostatin-1 to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenograft model. Clin. Cancer Res. 2000, 6, 4950-4956.
69. Strum, J.L.S.G.; Pauig, S.B.; Daniel, L.W. 1-[beta-D-arabinofuranosyl]cytosine stimulates ceramide and diglyceride formation in HL-60 cells. J. Biol. Chem. 1994, 269, 15493-15497.
70. Grant, S.; Jarvis, W.D.; Turner, A.J.; Wallace, H.J.; Pettit, G.R. Effects of bryostatin-1 and rGM-CSF on the metabolism of 1-beta-D-arabinofuranosylcytosine in human leukaemic myeloblasts. Br. J. Haematol. 1992, 82, 522-528.
71. Elgie, A.W.; Sargent, J.M.; Alton, P.; Peters, G.J.; Noordhuis, P.; Williamson, C.J.; Taylor, C.G. Modulation of resistance to ara-C by bryostatin-1 in fresh blast cells from patients with AML. Leuk. Res. 1998, 22, 373-378.
72. Grant, S.; Boise, L.; Westin, E.; Howe, C.; Pettit, G.R.; Turner, A.; McCrady, C. In vitro effects of bryostatin-1 on the metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine in human leukemia cells. Biochem. Pharmacol. 1991, 42, 853-867.
73. Jarvis, W.D.; Povirk, L.F.; Turner, A.J.; Traylor, R.S.; Gewirtz, D.A.; Pettit, G.R.; Grant, S. Effects of bryostatin-1 and other pharmacological activators of protein kinase C on 1-[beta-D-arabinofuranosyl]cytosine-induced apoptosis in HL-60 human promyelocytic leukemia cells. Biochem. Pharmacol. 1994, 47, 839-852.
74. Liu, K.Z.; Schultz, C.P.; Johnston, J.B.; Beck, F.W.; Al-Katib, A.M.; Mohammad, R.M.; Mantsch, H.H. Infrared spectroscopic study of bryostatin-1-induced membrane alterations in a B-CLL cell line. Leukemia 1999, 13, 1273-1280.
75. Beck, F.W.; Al-Katib, A.M.; Ahmad, I.; Wall, N.R.; Liu, K.Z.; Mantsch, H.H.; Mohammad, R.M. Bryostatin-1-induced modulation of nucleoside transporters and 2-chlorodeoxyadenosine influx in WSU-CLL cells. Int. J. Mol. Med. 2000, 5, 341-347.
76. Mohammad, R.M.; Beck, F.W.; Katato, K.; Hamdy, N.; Wall, N.; Al-Katib, A. Potentiation of 2-chlorodeoxyadenosine activity by bryostatin-1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5′-NT and Bax/Bcl-2. Biol. Chem. 1998, 379, 1253-1261.
77. Mohammad, R.M.; Limvarapuss, C.; Hamdy, N.; Dutcher, B.S.; Beck, F.W.; Wall, N.R.; Al-Katib, A.M. Treatment of a de novo fludarabine resistant-CLL xenograft model with bryostatin-1 followed by fludarabine. Int. J. Oncol. 1999, 14, 945-950.
78. Kaubisch, A.K.D.; Saltz, L., et al. Phase I trial of weekly sequential bryostatin-1 (Bryo), cisplatin, and paclitaxel in patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. 2000, 19, 230a.
79. Hickman, P.F.; Kemp, G.J.; Thompson, C.H.; Salisbury, A.J.; Wade, K.; Harris, A.L.; Radda, G.K. Bryostatin-1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study. Br. J. Cancer 1995, 72, 998-1003.
80. Prendiville, J.; Crowther, D.; Thatcher, N.; Woll, P.J.; Fox, B.W.; McGown, A.; Testa, N.; Stern, P.; McDermott, R.; Potter, M., et al. A phase I study of intravenous bryostatin-1 in patients with advanced cancer. Br. J. Cancer 1993, 68, 418-424.
81. Cheung, A.P.; Hallock, Y.F.; Vishnuvajjala, B.R.; Nguyenle, T.; Wang, E. Compatibility and stability of bryostatin-1 in infusion devices. Invest. New Drugs 1998, 16, 227-236.
82. Jayson, G.C.; Crowther, D.; Prendiville, J.; McGown, A.T.; Scheid, C.; Stern, P.; Young, R.; Brenchley, P.; Chang, J.; Owens, S., et al. A phase I trial of bryostatin-1 in patients with advanced malignancy using a 24 hour intravenous infusion. Br. J. Cancer 1995, 72, 461-468.
83. Philip, P.A.; Rea, D.; Thavasu, P.; Carmichael, J.; Stuart, N.S.; Rockett, H.; Talbot, D.C.; Ganesan, T.; Pettit, G.R.; Balkwill, F., et al. Phase I study of bryostatin-1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee. J. Natl. Cancer Inst. 1993, 85, 1812-1818.
84. Varterasian, M.L.; Mohammad, R.M.; Eilender, D.S.; Hulburd, K.; Rodriguez, D.H.; Pemberton, P.A.; Pluda, J.M.; Dan, M.D.; Pettit, G.R.; Chen, B.D.; Al-Katib, A.M. Phase I study of bryostatin-1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia. J. Clin. Oncol. 1998, 16, 56-62.
85. Marshall, J.I.J.M.; Rizvi, N., et al. Phase I trial of prolonged infusion bryostatin-1 in patients with advanced cancer. Proc. Am. Assoc. Cancer Res. 1998, 39, 601.
86. Langevin, A.M.B.M.; Kraft, A.S., et al. Phase I trial of bryostatin-1 in childhood solid tumors: a Pediatric Oncology Group (POG) study. Proc. Am. Soc. Clin. Oncol. 1998, 17, 206.
87. Weitman, S.; Langevin, A.M.; Berkow, R.L.; Thomas, P.J.; Hurwitz, C.A.; Kraft, A.S.; Dubowy, R.L.; Smith, D.L.; Bernstein, M. A phase I trial of bryostatin-1 in children with refractory solid tumors: a pediatric oncology group study. Clin. Cancer Res. 1999, 5, 2344-2348.
88. Institute, N.C. Drug products, bryostatin-1 (NSC 339555). Fact Sheet April 1, 1997.
89. Grant, S.; Roberts, J.; Poplin, E.; Tombes, M.B.; Kyle, B.; Welch, D.; Carr, M.; Bear, H.D. Phase Ib trial of bryostatin-1 in patients with refractory malignancies. Clin. Cancer Res. 1998, 4, 611-618.
90. Pavlick, A.C.H.A.; Liebes, L., et al. Bryostatin-1 and Cisplatin: a phase I and pharmacodynamic study. Proc. Am. Soc. Clin. Oncol. 2001, 20, a328.
91. Bangalore, N.S.B.S.; Bhargava, P., et al. Phase I study of bryostatin-1 and cisplatin in patients with advanced cancer. Proc. Am. Soc. Clin. Oncol. 2000, 19, a794,204a.
92. Lenz, H.J.G.M.; Xiong, Y.P., et al. Phase I study of bryostatin-1 and cisplatin (CDDP). Proc. Am. Soc. Clin. Oncol. 2000, 19, a795, 204a.
93. Dowlati, A.R.K.; Ksenich, P., et al. Phase I trial of combination of bryostatin-1 and vincristine in B-cell malignancies. Proc. Am. Soc. Clin. Oncol. 2000, 19, a837,215a.
94. Grant, S.C.L.; Smith, M.B., et al. Phase I trial of the signal transduction modulator bryostatin-1 (NSC 399555) and fludarabine in patients with progressive CLL and refractory indolent non-Hodgkin's lymphoma. Blood 2000, 93 Supplement 1, a590.
95. Propper, D.J.; Macaulay, V.; O'Byrne, K.J.; Braybrooke, J.P.; Wilner, S.M.; Ganesan, T.S.; Talbot, D.C.; Harris, A.L. A phase II study of bryostatin-1 in metastatic malignant melanoma. Br. J. Cancer. 1998, 78, 1337-1341.
96. Gonzalez, R.; Ebbinghaus, S.; Henthorn, T.K.; Miller, D.; Kraft, A.S. Treatment of patients with metastatic melanoma with bryostatin-1-a phase II study. Melanoma Res. 1999, 9, 599-606.
97. Bedikian, A.Y.; Plager, C.; Stewart, J.R.; O'Brian, C.A.; Herdman, S.K.; Ross, M.; Papadopoulos, N.; Eton, O.; Ellerhorst, J.; Smith, T. Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res. 2001, 11, 183-188.
98. Pagliaro, L.; Daliani, D.; Amato, R.; Tu, S.M.; Jones, D.; Smith, T.; Logothetis, C.; Millikan, R. A phase II trial of bryostatin-1 for patients with metastatic renal cell carcinoma. Cancer 2000, 89, 615-618.
99. Zonder, J.A.; Shields, A.F.; Zalupski, M.; Chaplen, R.; Heilbrun, L.K.; Arlauskas, P.; Philip, P.A. A phase II trial of bryostatin-1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res. 2001, 7, 38-42.
100. Blackhall, F.H.; Ranson, M.; Radford, J.A.; Hancock, B.W.; Soukop, M.; McGown, A.T.; Robbins, A.; Halbert, G.; Jayson, G.C. A phase II trial of bryostatin-1 in patients with non-Hodgkin's lymphoma. Br. J. Cancer 2001, 84, 465-469.
101. Brockstein, B.; Samuels, B.; Humerickhouse, R.; Arietta, R.; Fishkin, P. ; Wade, J.; Sosman, J.; Vokes, E.E. Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer. Invest. New Drugs 2001, 19, 249-254.
102. Varterasian, M.L.; Mohammad, R.M.; Shurafa, M.S.; Hulburd, K.; Pemberton, P.A.; Rodriguez, D.H.; Spadoni, V.; Eilender, D.S.; Murgo, A.; Wall, N.; Dan, M.; Al-Katib, A.M. Phase II trial of bryostatin-1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Clin. Cancer Res. 2000, 6, 825-828.
103. Ilson, D.S.M.; O'reilly, E.; Kelsen, D.; Welch, M.; Kaubisch, A.; Schwartz, G.K. A phase II trial of weekly one-hour paclitaxel followed by bryostatin-1 in patients with advanced esophageal cancer: an active new drug combination. Proc. Am. Soc. Clin. Oncol. 2001, 20, a633,159.
104. Charoentum, C.M.A.; Gajewski, T.F., et al. Phase II study of bryostatin-1 in combination with paclitaxel for advanced non-small cell lung cancer (NSCLC). Proc. Am. Soc. Clin. Oncol. 2001, 20, a2834.
105. Tuttle, T.M.; Inge, T.H.; Bethke, K.P.; McCrady, C.W.; Pettit, G.R.; Bear, H.D. Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin-1. Cancer Res. 1992, 52, 548-553.
106. Tuttle, T.M.; Bethke, K.P.; Inge, T.H.; McCrady, C.W.; Pettit, G.R.; Bear, H.D. Bryostatin-1-activated T cells can traffic and mediate tumor regression. J. Surg. Res. 1992, 52, 543-548.
107. Tuttle, T.M.; Inge, T.H.; Lind, D.S.; Bear, H.D. Adoptive transfer of bryostatin-1-activated T cells provides long-term protection from tumour metastases. Surg. Oncol. 1992, 1, 299-307.
108. Tuttle, T.M.; McCrady, C.W.; Inge, T.H.; Salour, M.; Bear, H.D. Gamma-interferon plays a key role in T-cell-induced tumor regression. Cancer Res. 1993, 53, 833-839.
109. Tuttle, T.M.; Inge, T.H.; Wirt, C.P.; Frank, J.L.; McCrady, C.M.; Bear, H.D. Bryostatin-1 activates T cells that have antitumor activity. J. Immunother. 1992, 12, 75-81.
110. Baldwin, N.G.; Rice, C.D.; Tuttle, T.M.; Bear, H.D.; Hirsch, J.I.; Merchant, R.E. Ex vivo expansion of tumor-draining lymph node cells using compounds which activate intracellular signal transduction. I. Characterization and in vivo anti-tumor activity of glioma-sensitized lymphocytes. J. Neurooncol. 1997, 32, 19-28.
111. Rice, C.D.; Baldwin, N.G.; Biron, R.T.; Bear, H.D.; Merchant, R.E. Ex vivo expansion of tumor-draining lymph node cells using compounds which activate intracellular signal transduction. II. Cytokine production and in vivo efficacy of glioma-sensitized lymphocytes. J. Neurooncol. 1997, 32, 29-38.
112. Chin, C.S.; Graham, L.J.; Hamad, G.G.; George, K.R.; Bear, H.D. Bryostatin-1/ionomycin-activated T cells mediate regression of established tumors. J. Surg. Res. 2001, 98, 108-115.
113. Fleming, M.D.; Bear, H.D.; Lipshy, K.; Kostuchenko, P.J.; Portocarero, D.; McFadden, A.W.; Barrett, S.K. Adoptive transfer of bryostatin-1-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro. J. Immunother. Emphas. Immunol. 1995, 18, 147-155.
114. Lind, D.S.; Tuttle, T.M.; Bethke, K.P.; Frank, J.L.; McCrady, C.W.; Bear, H.D. Expansion and tumour specific cytokine secretion of bryostatin-1-activated T-cells from cryopreserved axillary lymph nodes of breast cancer patients. Surg. Oncol. 1993, 2, 273-282.
115. Bear, H.D.; Roberts, J.; Cornell, D.; Tombes, M.B.; Kyle, B. Adoptive immunotherapy of cancer with pharmacologically activated lymph node lymphocytes: a pilot clinical trial. Cancer Immunol. Immunother. 2001, 50, 269-274.
116. van der Hem, K.G.; Drager, A.M.; Odding, J.H.; Langenhuijsen, M.M.; Huijgens, P.C. Bryostatin-1-5 stimulates normal human hematopoiesis and inhibits proliferation of HL60 leukemic cells. Leuk. Res. 1995, 19, 7-13.
117. van der Hem, K.G.; Drager, A.M.; Odding, J.H.; Huijgens, P.C. Effects of bryostatin-1-5 and hematopoietic growth factors on acute myeloid leukemia cell differentiation, proliferation, and primary plating efficiency. Leuk. Res. 1995, 19, 651-657.
118. Kraft, A.S.; Woodley, S.; Pettit, G.R.; Gao, F.; Coll, J.C.; Wagner, F. Comparison of the antitumor activity of bryostatin-1s 1, 5, and 8. Cancer Chemother. Pharmacol. 1996, 37, 271-278.
119. Bignami, G.S.; Wagner, F.; Grothaus, P.G.; Rustagi, P.; Davis, D.E.; Kraft, A.S. Biological activity of 26-succinylbryostatin-1. Biochim. Biophys. Acta 1996, 1312, 197-206.