In the five decades since camptothecin was first isolated from the bark of a tree used in traditional Chinese medicine and identified as a powerful anticancer agent, several thousand chemicals with similar structures and functions have been investigated. And while two of these analog compounds, irinotecan and topotecan, have been approved in the U.S. as treatments for cancer, both are associated with significant shortcomings. Researchers from Roswell Park Cancer Institute (RPCI) have reported findings about a new synthetic form of camptothecin, known as FL118, that appears to have greater potency, longer efficacy and fewer adverse side effects than irinotecan and topotecan.
Writing in the American Journal of Translational Research, a team led by Fengzhi Li, PhD, of the Roswell Park Department of Pharmacology and Therapeutics has documented the findings of their latest preclinical study of FL118, which was shown to effectively eliminate human colon and head-and-neck xenograft tumors that were developed to be resistant to both irinotecan and topotecan.
"We knew from our previous research that FL118 can overcome treatment resistance resulting from overexpression of ABCG2, a key transport protein. Now we have demonstrated that FL118 is also able to conquer irinotecan and topotecan resistance — a well-known challenge in clinical practice — and have delineated processes that explain FL118's unique mechanisms and characteristics," says Dr. Li, the paper's senior author.
The scientists demonstrate that:
•FL118 is not a substrate, or reactive target, for ABCG2 or MDR1 (multiple drug resistance protein 1, also known as P-gp) and may also not be a substrate for other efflux pump proteins; it rapidly clears from the circulation but accumulates in tumors, remaining there for extended periods.
•In contrast to irinotecan, it is possible to administer FL118 orally, without the need to add an efflux-pump protein inhibitor.
•SN-38, an active metabolic form of irinotecan, and topotecan are anywhere from 10 times to 100 times less effective than FL118 in eliminating the downstream oncogenic targets of FL118 — survivin, Mcl-1, XIAP and/or cIAP2.
•It appears that FL118, unlike irinotecan and topotecan, is effective after multiple cycles of administration, without generating treatment resistance.
Taken together with findings reported by this team in the journal Cancer Research in December 2014 regarding FL118's ability to stimulate the death of cancer cells through accumulation of p53 and depletion of MdmX, the study provides additional support for further development of this novel anticancer agent for clinical applications.
"We believe FL118 may prove to be effective against a number of solid and liquid tumors with defined genetic alterations, such as p53 mutation and overexpression of the ABCG2, MDR1 and/or MdmX proteins, and we look forward to further exploring these processes in the first studies of FL118 in patients in the near future," Dr. Li adds.
Roswell Park Cancer Institute (RPCI)