Abstract
The time- and dose-dependent effects of recombinant human interleukin 1α (IL-1α) on the antitumor activity of mitomycin C (MMC) and porfiromycin (PORF) were studied in RIF-1 and Panc02 solid tumor model systems. IL-1α produced dose-dependent sensitization of clonogenic RIF-1 tumor cells to MMC in vivo. IL-1α chemosensitization was highly schedule dependent, and the most efficacious schedules produced dose-modifying factors of 3.6 and 5.1 for MMC and PORF, respectively. More than additive clonogenic cell kill after IL-1α-chemotherapy combinations reflected increased cellular sensitivity to MMC and PORF. The combinations also produced marked decreases in the yield of viable tumor cells, suggesting that the bioreductive drugs may have also potentiated the microvascular injury and ischemia produced by IL-1α. Dexamethasone inhibited and ketoconazole, an inhibitor of corticosterone biosynthesis, enhanced IL-1α-mediated chemosensitization in these models. IL-1α mediated chemosensitization to MMC, and PORF was also demonstrated by tumor growth inhibition in the RIF-1 model and increased survival of mice in the spontaneously metastasizing Panc02 system. Chemosensitization of bone marrow spleen colony-forming units was not seen. IL-1α (1000 units/ml) had no effect on MMC and PORF cytotoxicity in RIF-1 and PORF cell lines in vitro. The results indicate that the tumor-specific IL-1α-induced pathophysiologies can sensitize solid tumors to agents which are preferentially activated, retained, and cytotoxic to cells under hypoxic conditions. Our results suggest that strategies combining bioreductively activated hypoxic cell cytotoxins and biological agents might offer efficacious alternatives or adjuvants to conventional combination approaches.
| Original language | English |
|---|---|
| Pages (from-to) | 5454-5460 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 51 |
| Issue number | 20 |
| State | Published - Oct 15 1991 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Potentiation of mitomycin C and porfiromycin antitumor activity in solid tumor models by recombinant human interleukin 1α. / Braunschweiger, Paul G; Jones, Steven A.; Johnson, Candace S.; Furmanski, Philip.
In: Cancer Research, Vol. 51, No. 20, 15.10.1991, p. 5454-5460.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Potentiation of mitomycin C and porfiromycin antitumor activity in solid tumor models by recombinant human interleukin 1α
AU - Braunschweiger, Paul G
AU - Jones, Steven A.
AU - Johnson, Candace S.
AU - Furmanski, Philip
PY - 1991/10/15
Y1 - 1991/10/15
N2 - The time- and dose-dependent effects of recombinant human interleukin 1α (IL-1α) on the antitumor activity of mitomycin C (MMC) and porfiromycin (PORF) were studied in RIF-1 and Panc02 solid tumor model systems. IL-1α produced dose-dependent sensitization of clonogenic RIF-1 tumor cells to MMC in vivo. IL-1α chemosensitization was highly schedule dependent, and the most efficacious schedules produced dose-modifying factors of 3.6 and 5.1 for MMC and PORF, respectively. More than additive clonogenic cell kill after IL-1α-chemotherapy combinations reflected increased cellular sensitivity to MMC and PORF. The combinations also produced marked decreases in the yield of viable tumor cells, suggesting that the bioreductive drugs may have also potentiated the microvascular injury and ischemia produced by IL-1α. Dexamethasone inhibited and ketoconazole, an inhibitor of corticosterone biosynthesis, enhanced IL-1α-mediated chemosensitization in these models. IL-1α mediated chemosensitization to MMC, and PORF was also demonstrated by tumor growth inhibition in the RIF-1 model and increased survival of mice in the spontaneously metastasizing Panc02 system. Chemosensitization of bone marrow spleen colony-forming units was not seen. IL-1α (1000 units/ml) had no effect on MMC and PORF cytotoxicity in RIF-1 and PORF cell lines in vitro. The results indicate that the tumor-specific IL-1α-induced pathophysiologies can sensitize solid tumors to agents which are preferentially activated, retained, and cytotoxic to cells under hypoxic conditions. Our results suggest that strategies combining bioreductively activated hypoxic cell cytotoxins and biological agents might offer efficacious alternatives or adjuvants to conventional combination approaches.
AB - The time- and dose-dependent effects of recombinant human interleukin 1α (IL-1α) on the antitumor activity of mitomycin C (MMC) and porfiromycin (PORF) were studied in RIF-1 and Panc02 solid tumor model systems. IL-1α produced dose-dependent sensitization of clonogenic RIF-1 tumor cells to MMC in vivo. IL-1α chemosensitization was highly schedule dependent, and the most efficacious schedules produced dose-modifying factors of 3.6 and 5.1 for MMC and PORF, respectively. More than additive clonogenic cell kill after IL-1α-chemotherapy combinations reflected increased cellular sensitivity to MMC and PORF. The combinations also produced marked decreases in the yield of viable tumor cells, suggesting that the bioreductive drugs may have also potentiated the microvascular injury and ischemia produced by IL-1α. Dexamethasone inhibited and ketoconazole, an inhibitor of corticosterone biosynthesis, enhanced IL-1α-mediated chemosensitization in these models. IL-1α mediated chemosensitization to MMC, and PORF was also demonstrated by tumor growth inhibition in the RIF-1 model and increased survival of mice in the spontaneously metastasizing Panc02 system. Chemosensitization of bone marrow spleen colony-forming units was not seen. IL-1α (1000 units/ml) had no effect on MMC and PORF cytotoxicity in RIF-1 and PORF cell lines in vitro. The results indicate that the tumor-specific IL-1α-induced pathophysiologies can sensitize solid tumors to agents which are preferentially activated, retained, and cytotoxic to cells under hypoxic conditions. Our results suggest that strategies combining bioreductively activated hypoxic cell cytotoxins and biological agents might offer efficacious alternatives or adjuvants to conventional combination approaches.
UR - http://www.scopus.com/inward/record.url?scp=0025937469&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025937469&partnerID=8YFLogxK
M3 - Article
VL - 51
SP - 5454
EP - 5460
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 20
ER -