The purpose of the proposed research is to synthesize a series of peptide derivatives of the antitumor drug actinomycin D (AMD). They will be tested in prodrug and targeting strategies aimed at improving tumor specificity. The title compounds will consist of short peptides (3-5 amino acids) attached amide-wise to the AMD chromophoric amino group. A method has been developed to synthesize such novel compounds, which, unlike AMD itself, do not bind to DNA. A peptidyl-actinomycin will act as a prodrug if cleaved to AMD by an enzyme found at higher levels in tumor than normal tissue. Proposed examples are Glu (Delta)-Gly-Pro- (AMD) and D-Val-Leu-lys-Val-Pro-(AMD) which should be cleaved by delta-glutamyl transferase (GGT) and plasmin respectively. Such cleavage would afford the dipeptidyl-actinomycin which will spontaneously cyclize to the diketopiperazine and AMD. This would circumvent the reported difficulty with some peptidyl- drugs that they are not substrates for the enzyme. GGT is increased in human tumors of the liver, colon and breast; plasmin is associated with many solid tumors. The GGT-activated prodrugs will be tested in various cell lines with high or low GGT levels. They and the plasmin-activated prodrugs will be submitted to NCI for test in tumor-bearing animals. For targeting, conjugation of other peptidyl-AMD's (designed for cleavage to AMD by lysosomal enzymes) with monoclonal antibodies to specific tumor cells will be undertaken. To increase the AMD/antibody ratio, conjugates will also be prepared by linking antibody to human serum albumin after conjugating the latter with many molecules of peptidyl-AMD. These targeting approaches will be tested initially in vitro in appropriate human tumor cell lines and subsequently in tumor bearing animals. In vitro testing will include cell viability assays in human leukemia cell lines after exposure to the peptidyl-AMD-antibody conjugates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA011627-22
Application #
3163505
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-03-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
22
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Washington Hospital Center
Department
Type
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20010
Nishino, Mizuki; Dahlberg, Suzanne E; Fulton, Linnea E et al. (2016) Volumetric Tumor Response and Progression in EGFR-mutant NSCLC Patients Treated with Erlotinib or Gefitinib. Acad Radiol 23:329-36
Nishino, Mizuki; Cardarella, Stephanie; Dahlberg, Suzanne E et al. (2015) Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival. Eur J Radiol 84:998-1004
Nishino, M; Jackman, D M; DiPiro, P J et al. (2014) Revisiting the relationship between tumour volume and diameter in advanced NSCLC patients: An exercise to maximize the utility of each measure to assess response to therapy. Clin Radiol 69:841-8
Nishino, Mizuki; Itoh, Harumi; Hatabu, Hiroto (2014) A practical approach to high-resolution CT of diffuse lung disease. Eur J Radiol 83:6-19
Nishino, Mizuki; Dahlberg, Suzanne E; Cardarella, Stephanie et al. (2013) Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR mutations during EGFR-tyrosine kinase inhibitor therapy: developing criteria to continue therapy beyond RECIST progression. Cancer 119:3761-8
Nishino, Mizuki; Cardarella, Stephanie; Jackman, David M et al. (2013) RECIST 1.1 in NSCLC patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors: comparison with RECIST 1.0. AJR Am J Roentgenol 201:W64-71
Nishino, Mizuki; Dahlberg, Suzanne E; Cardarella, Stephanie et al. (2013) Tumor volume decrease at 8 weeks is associated with longer survival in EGFR-mutant advanced non-small-cell lung cancer patients treated with EGFR TKI. J Thorac Oncol 8:1059-68
Nishino, Mizuki; Cardarella, Stephanie; Dahlberg, Suzanne E et al. (2013) Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors. Lung Cancer 79:283-8
Nishino, Mizuki; Jagannathan, Jyothi P; Krajewski, Katherine M et al. (2012) Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR Am J Roentgenol 198:737-45
Shinagare, Atul B; Okajima, Yuka; Oxnard, Geoffrey R et al. (2012) Unsuspected pulmonary embolism in lung cancer patients: comparison of clinical characteristics and outcome with suspected pulmonary embolism. Lung Cancer 78:161-6

Showing the most recent 10 out of 22 publications