Flavopiridol increases therapeutic ratio of radiotherapy by preferentially enhancing tumor radioresponse.
OBJECTIVE
Recently we reported that inhibition of cyclin-dependent kinases (cdks) by flavopiridol enhanced the radiation response of murine ovarian carcinoma cells in culture. The purpose of this investigation was to extend these studies to in vivo tumor models and test whether flavopiridol increases the therapeutic ratio of radiotherapy.


METHODS
Three transplantable syngeneic mouse tumors were used: mammary carcinoma (MCa-29), ovarian carcinoma (OCa-I), and a lymphoma (Ly-TH). Tumor treatment endpoints included growth delay, cure, and spontaneous lung metastases (OCa-I tumor). The normal tissue endpoint was survival of jejunal crypt cells quantified microscopically. A range of flavopiridol doses from 0.625 to 5.0 mg/kg were given systemically once or twice daily over 5, 10, or 20 days. Combined therapy flavopiridol treatments were initiated either several days before or shortly after the start of single dose or daily fractionated radiotherapy.


RESULTS
The major findings of this study are that all three tumors treated with flavopiridol alone responded by tumor growth delay. Two of the tumors (MCa-29 and Ly-TH) responded in a schedule-dependent manner with larger radiation enhancement factors when flavopiridol treatment was started a few hours after irradiation (radioenhancement factors [EF] Ly-TH = 2.04, EF MCa-29 = 1.50 for single dose irradiation). When combined with fractionated irradiation (2.6 Gy daily for 10 or 20 days), flavopiridol enhanced the response of the MCa-29 tumor by a factor of 1.25-1.46. A fractional radiation dose of 6 Gy in combination with flavopiridol produced a 62.5% cure rate compared with 25% tumor cure for radiation alone. A novel finding of this study was the demonstration of antimetastatic activity of flavopiridol in addition to its effect on the local primary tumor. Both the incidence and absolute number of lung metastasis were reduced when flavopiridol followed surgical removal of the large (10 mm) primary leg tumor. The normal jejunum treated with flavopiridol and radiation responded in a schedule independent manner and the degree of radioenhancement (EF, 1.05-1.06) was much less than for any of the tumors studied.


CONCLUSIONS
Therapeutic gain was achieved when flavopiridol treatment was initiated either before or after the start of radiotherapy. Flavopiridol shows promising clinical potential administered alone or in combination with other cytotoxic agents, including both chemotherapy and radiotherapy.
Mason
Kathy A
KA
Department of Experimental Radiation Oncology-66, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. kmason@mdanderson.org
Hunter
Nancy R
NR
Raju
Uma
U
Ariga
Hisanori
H
Husain
Amir
A
Valdecanas
David
D
Neal
Robert
R
Ang
Kian K
KK
Milas
Luka
L
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D019583:Dose Fractionation, Radiation; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use*; D007583:Jejunum / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008809:Mice, Inbred C3H; D010051:Ovarian Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D010880:Piperidines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011838:Radiation-Sensitizing Agents; C077990:alvocidib; D018844:Cyclin-Dependent Kinases