A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit α of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors

Clinical Cancer Research

Volumn 9, Issue 11, 2003, Pages 4069-4076

  Goel, Sanjay ^a   Desai, Kavita ^a   Bulgaru, Anca ^a   Fields, Abbie ^a   Goldberg, Gary ^a   Agrawal, Sudhir ^b   Martin, Russell ^b   Grindel, Michael ^c   Mani, Sridhar ^a,d  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b HYBRIDON INC   (United States)

^c EPD Pharma Solutions   (United States)

^d Jack D Weiler Hospital   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ANTISENSE OLIGONUCLEOTIDE; ASPARTATE AMINOTRANSFERASE; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYTOTOXIC AGENT; DOCETAXEL; FOMIVIRSEN; GENE EXPRESSION MODULATOR 231; HYB0165; IRINOTECAN; ISIS 3521; MESSENGER RNA; OBLIMERSEN; PROTEIN BCL 2; PROTEIN KINASE C ALPHA; UNCLASSIFIED DRUG; VITRAVINE;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BLEEDING; BLOOD TOXICITY; CHRONIC DRUG ADMINISTRATION; CLINICAL ARTICLE; CLINICAL TRIAL; CONTINUOUS INFUSION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CORRELATION ANALYSIS; DISEASE SEVERITY; DOSE RESPONSE; DRUG DOSE REGIMEN; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DRUG WITHDRAWAL; ENZYME SUBUNIT; ESOPHAGITIS; FATIGUE; FEMALE; FEVER; FLU LIKE SYNDROME; HUMAN; HYPERBILIRUBINEMIA; HYPERGLYCEMIA; HYPOTENSION; LIVER TOXICITY; MALE; MAXIMUM TOLERATED DOSE; MUCOSA INFLAMMATION; MYALGIA; NAUSEA; NEUTROPENIA; OPEN STUDY; PARTIAL THROMBOPLASTIN TIME; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; POLYURIA; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REFLUX ESOPHAGITIS; SIDE EFFECT; SOLID TUMOR; ST SEGMENT ELEVATION; THROMBOCYTOPENIA; VOMITING; XEROSTOMIA;

AGED; AGED, 80 AND OVER; CYCLIC AMP-DEPENDENT PROTEIN KINASES; FEMALE; HEMATOLOGIC DISEASES; HUMANS; INFUSIONS, INTRAVENOUS; MALE; MIDDLE AGED; NEOPLASMS; OLIGONUCLEOTIDES; PROTEIN SUBUNITS;

EID: 0141678916     PISSN: 10780432     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (31)

1. De Smet, M. D., Meenke, C. J., and Van den Hoem, G. J. Formivirsen: a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul. Immunol. Inflamm., 7: 189-198, 1999.
2. Crooke, S. T. Potential role of antisense technology in oncology. Oncogene, 19: 6651-6659, 2000.
3. Agrawal, S., and Kandimalla, E. R. Antisense therapeutics: is it as simple as complementary base recognition? Mol. Med. Today, 2: 72-81, 2000.
4. Wang, H., Prasad, G., Buolamwini, J. K., and Zhang, R. Antisense anticancer oligonucleotide therapeutics. Curr. Cancer Drug Targets, 3: 177-196, 2001.
5. Agrawal, S., and Kandimalla, E. R. Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr. Cancer Drug Targets, 3: 197-209, 2001.
6. Chen, H. X., Marshall, J. L., Ness, E., Martin, R. R., Dvorchik, B., Rizvi, N., Marquis, J., McKinlay, M., Dahut, W., and Hawkins, M. J. A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors. Clin. Cancer Res., 4: 1259-1266, 2000.
7. Bansal, R., Chen, H. X., Marshall, J. L., Tan, J., Glazer, R. I., and Wainer, I. W. Detection of a mixed-backbone oligonucleotide (GEM 231) in liver and tumor tissues by capillary electrophoresis. J. Chromatogr. B Biomed. Sci. Appl., 750: 129-135, 2001.
8. Amieux, P. S., and McKnight, G. S. The essential role of RI α in the maintenance of regulated PKA activity. Ann. N. Y. Acad. Sci., 968: 75-95, 2002.
9. Tortora, G., and Ciardiello, F. Protein kinase A as target for novel integrated strategies of cancer therapy. Ann. N. Y. Acad. Sci., 968: 139-147, 2002.
10. Miller, W. R. Regulatory subunits of PKA and breast cancer. Ann. N. Y. Acad. Sci., 968: 37-48, 2002.
11. Miller, W. R., Hulme, M. J., Bartlett, J. M., MacCallum, J., and Dixon, J. M. Changes in messenger RNA expression of protein kinase A regulatory subunit α in breast cancer patients treated with tamoxifen. Clin. Cancer Res., 3: 2399-2404, 1997.
12. Srivastava, R. K., Srivastava, A. R., Park, Y. G., Agrawal, S., and Cho-Chung, Y. S. Antisense depletion of RIα subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells. Breast Cancer Res. Treat., 49: 97-107, 1998.
13. Wang, H., Hang, J., Shi, Z., Li, M., Yu, D., Kandimalla, E. R., Agrawal, S., and Zhang, R. Antisense oligonucleotide targeted to RIα subunit of cAMP-dependent protein kinase (GEM231) enhances therapeutic effectiveness of cancer chemotherapeutic agent irinotecan in nude mice bearing human cancer xenografts: in vivo synergistic activity, pharmacokinetics and host toxicity. Int. J. Oncol., 21: 73-80, 2002.
14. Cho, Y. S., Kim, M. K., Tan, L., Srivastava, R., Agrawal, S., and Cho-Chung, Y. S. Protein kinase A RIα antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. Clin. Cancer Res., 8: 607-614, 2002.
15. Nesterova, M., and Cho-Chung, Y. S. Oligonucleotide sequence-specific inhibition of gene expression, tumor growth inhibition, and modulation of cAMP signaling by an RNA-DNA hybrid antisense targeted to protein kinase A RIα subunit. Antisense Nucleic Acid Drug Dev., 6: 423-33, 2000.
16. Wang, H., Cai, Q., Zeng, X., Yu, D., Agrawal, S., and Zhang, R. Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIα subunit of protein kinase A after oral administration. Proc. Natl. Acad. Sci. USA, 24: 13989-13994, 1999.
17. Agrawal, S., Kandimalla, E. R., Yu, D., Ball, R., Lombardi, G., Lucas, T., Dexter, D. L., Hollister, B. A., and Chen, S. F. GEM 231, a second-generation antisense agent complementary to protein kinase A RIα subunit, potentiates antitumor activity of irinotecan in human colon, pancreas, prostate and lung cancer xenografts. Int. J. Oncol., 21: 65-72, 2002.
18. Simon, R., Freidlin, B., Rubinstein, L., Arbuck, S. G., Collins, J., and Christian, M. C. Accelerated titration designs for Phase I clinical trials in oncology. J. Natl. Cancer Inst. (Bethesda), 89: 1138-1147, 1997.
19. Waters, J. S., Webb, A., Cunningham, D., Clarke, P. A., Raynaud, F., di Stefano, F., and Cotter, F. E. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J. Clin. Oncol., 18: 1812-1823, 2000.
20. Mani, S., Gu, Y., Wadler, S., and Fingert, H. Antisense therapeutics in oncology: points to consider in their clinical evaluation. Antisense Nucleic Acid Drug Dev., 9: 543-547, 1999.
21. Sheehan, J. P., and Lan, H. C. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood, 92: 1617-1625, 1998.
22. Henry, S. P., Geary, R. S., Yu, R., and Levin, A. A. Drug properties of second-generation antisense oligonucleotides: how do they measure up to their predecessors? Curr. Opin. Investig. Drug, 10: 1444-1449, 2001.
23. Tamm, I., Dorken, B., and Hartmann, G. Antisense therapy in oncology: new hope for an old idea. Lancet, 358: 489-497, 2001.
24. Holmlund, J. T., Monia, B. P., Kwoh, T. J., and Dorr, F. A. Toward antisense oligonucleotide therapy for cancer: ISIS compounds in clinical development. Curr. Opin. Mol. Ther., 3: 372-385, 1999.
25. Rudin, C. M., Holmlund, J., Fleming, G. F., Mani, S., Stadler, W. M., Schumm, P., Monia, B. P., Johnston, J. F., Geary, R., Yu, R. Z., Kwoh, T. J., Dorr, F. A., and Ratain, M. J. Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. Clin. Cancer Res., 7: 1214-1220, 2001.
26. Cripps, M. C., Figueredo, A. T., Oza, A. M., Taylor, M. J., Fields, A. L., Holmlund, J. T., McIntosh, L. W., Geary, R. S., and Eisenhauer, E. A. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin. Cancer Res., 8: 2188-2192, 2002.
27. Tolcher, A. W., Reyno, L., Venner, P. M., Ernst, S. D., Moore, M., Geary, R. S., Chi, K., Hall, S., Walsh, W., Dorr, A., and Eisenhauer, E. A randomized Phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin. Cancer Res., 8: 2530-2535, 2002.
28. Mani, S., Rudin, C. M., Kunkel, K., Holmlund, J. T., Geary, R. S., Kindler, H. L., Dorr, F. A., and Ratain, M. J. Phase I clinical and pharmacokinetic study of protein kinase C-α antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer. Clin. Cancer Res., 8: 1042-1048, 2002.
29. Goel, S., Bulgaru, A., Desai, K., Martin, R. R., McKinlay, M., and Mani, S. Phase I trial using GEM®231, a second-generation antisense oligonucleotide targeting protein kinase A (PKA) RIα, in combination with docetaxel in patients with advanced solid cancers. Proc. Am. Soc. Clin. Oncol., 22: 210, 2003.
30. Klasa, R. J., Gillum, A. M., Klem, R. E., and Frankel, S. R. Oblimersen: Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev., 12: 193-213, 2002.
31. Herbst, R. S. Targeted therapy in non-small-cell lung cancer. Oncology (Huntingt.), 16 (Suppl. 9): 19-24, 2002.