Adriamycin (AdR) and related anthracyclines are important antitumor agents in the management of human malignancies. Their clinical use is compromised by slow intracellular transport, dose limiting cardiotoxicity and emergence of drug resistance. Our work has focused on studies related to the mechanism of action of and cellular resistance to AdR and some of its newer clinically important analogs both in vitro and in vivo. We have developed and modified techniques which allow us to study AdR transport and resistance, cytokinetic effects and cytotoxicity in individual cells and sub-populations from heterogeneous solid tumors.
The specific aims of this continuation proposal are: To correlate intracellular anthracycline fluorescence with effects on clonogenicity of drug sensitive and resistant cells, sub-populations from heterogeneous tumors and in relation to cell cycle phase and proliferation status. To analyze effect of selected drugs used in combination chemotherapy on anthracycline transport and cytotoxicity. To study correlation between easily measurable parameters such as cell size, nuclear/cytoplasmic ratio, DNA, RNA, protein content, presence or absence of drug resistance-related proteins, and tumor associated antigens and intracellular anthracycline transport characteristics. These parameters will be used for isolation of sub-populations for further study in soft agar and as xenografts. From the planned studies, we will obtain data which will allow us to better understand the relation between transport, role of drug resistance related proteins and the response of sub-populations in a heterogeneous solid tumor to anthracyclines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029360-05
Application #
3168681
Study Section
(SSS)
Project Start
1980-12-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101
Ramachandran, C; Kunikane, H; You, W et al. (1998) Phorbol ester-induced P-glycoprotein phosphorylation and functionality in the HTB-123 human breast cancer cell line. Biochem Pharmacol 56:709-18
Ramachandran, C; You, W; Krishan, A (1997) Bcl-2 and mdr-1 gene expression during doxorubicin-induced apoptosis in murine leukemic P388 and P388/R84 cells. Anticancer Res 17:3369-76
Mou, C; Ganju, N; Sridhar, K S et al. (1997) Simultaneous quantitation of plasma doxorubicin and prochlorperazine content by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 703:217-24
Krishan, A; Fitz, C M; Andritsch, I (1997) Drug retention, efflux, and resistance in tumor cells. Cytometry 29:279-85
Kunikane, H; Zalupski, M M; Ramachandran, C et al. (1997) Flow cytometric analysis of P-glycoprotein expression and drug efflux in human soft tissue and bone sarcomas. Cytometry 30:197-203
Isobe, H; Sridhar, K S; Doria, R et al. (1995) Prognostic significance of DNA aneuploidy in diffuse malignant mesothelioma. Cytometry 19:86-91
Ramachandran, C; Mead, D; Wellham, L L et al. (1995) Expression of drug resistance-associated mdr-1, GST pi, and topoisomerase II genes during cell cycle traverse. Biochem Pharmacol 49:545-52
Isobe, H; Wellham, L; Sauerteig, A et al. (1994) Doxorubicin retention and chemoresistance in human mesothelioma cell lines. Int J Cancer 57:581-5
Sridhar, K S; Krishan, A; Samy, T S et al. (1994) Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker. Cancer Chemother Pharmacol 34:377-84
Ramachandran, C; Samy, T S; Huang, X L et al. (1993) Doxorubicin-induced DNA breaks, topoisomerase II activity and gene expression in human melanoma cells. Biochem Pharmacol 45:1367-71

Showing the most recent 10 out of 22 publications