SBIR-STTR Award

After obtaining 80% cures of advanced tumors with Cytochlor/Cytofluor and 2 biomodulators, without side effects, in studies involving the radiation of 5 rodent tumors, the applicants conducted pilot studies with 5 human tumors in nude mice and achieved an average of 80% control of 1 glioblastoma, 1 lung, 1 breast and 2 prostate tumors. Their goals with 3 tumors: a) simplify the protocol with emphasis on CldC and H4U alone, b) compare: 1) slow release pellets with bolus doses, 2) CldC and IdU and BrdU (the first generation drugs), and 3) two radiosensitizers moving towards or in clinical trial. The end points will be days in tumor regrowth delay and number of cures. The applicants propose to determine a) the fraction of tumor cells containing CldU in their DNA, b) normal tissue damage to intestine, c) the capacity of CldC and FdC to restore silenced cad- cell lines to cad+ by hypomethylation. dCMP deaminase and dC kinase, enzymes which drive the selectivity of the technology, are elevated in many human tumors. The level of these enzymes in human tumor xenograftline and in human tumors and normal tissues will be examined with an emphasis of tumors of the head and neck and associated normal tissue from patients. PROPOSED COMMERCIAL APPLICATION: Radiation centers throughout the world which treat more than 60% of all cancer patients, are in search of a drug that will allow more aggressive treatment of cancer. The technology exploits the elevation of enzymes, important for success of the tumor, for a therapeutic advantage. The technology results in a 3-fold dose increase, so that cures with a real impact on survival can be obtained; e.g. a dose of 70 Gy will be as effective as a 210 Gy to the tumor without normal tissue damage. The world-wide patented invention will earn $60 million per year. The NCI has gound that the drug is not toxic to mice, dogs, and monkeys. Together with the cooperation of the NCI, we are about to launch a Phase I clinical trial with a simplified protocol utilizing only Cytochlor and one biomodulator.

Cytochlor Technology is about to enter a Phase I trial as a radiosensitizer of tumors of the oral cavity and oropharynx with NCI supervision. Our objective is to demonstrate Cytochlor's safety, selectivity and possible efficacy (although efficacy is not the goal of a Phase I trial). Our goal is to move Cytochlor Technology to a mutliinstitutional Phase II clinical trial, clinical practice and commercialization. We hypothesize that the elevation of dC kinase and dCMP deaminase in tumors can be exploited for a therapeutic advantage to obtain selective radiosensitization of human tumors with Cytochlor (5-chlorodeoxycytidine) and Tetrahydrouridine. We have been given a starting dose (60 mg/m2/day) based on toxicity studies in primates receiving 5-Chlorodeoxycytidine (CldC) and Tetrahydrouridine (H4U) 5 days a week for 3 weeks in which no clinical signs of toxicity were observed. H4U will be utilized at a fixed dose of 1500mg/m2/day. Patients will be entered into the trial if levels of deoxycytidine kinase and dCMP deaminase in tumors exceeds (>2.5) the levels in adjacent normal tissue. Laboratory studies will be conducted that are associated with the clinical trial including pharmacokinetic studies and metabolic monitoring of patient serum and urine with respect to levels of CldC, 5-chlorodeoxyuridine, and 5-chlorouracil. As clinical endpoints are carefully evaluated, the % of cells incorporating 5-chlorouracil (ClUra) derived from CldC and the replacement of thymiine by CdlUra in tumor and normal tissue DNA will be determined to monitor the tumor selectivity, which is the hallmark of this enzyme-driven technology as dose escalation proceeds in the Phase I trial. We will also determine the relative effectiveness with which H4U inhibits the cytidine deaminase of tumor and normal tissue. We will determine whether the enzyme profile of glioblastoma and tumors of the prostate, rectum, breast, and uterus have the ideal enzyme profile as shown for H/N tumors (elevations of deoxycytidine kinase and dCMP deaminase) as a first step in demonstrating the universal or broader application of Cytochlor Technology.

Thesaurus Terms:
antimetabolite, dCMP deaminase, deoxycytidine, drug screening /evaluation, enzyme activity, phosphotransferase, protein metabolism, radiosensitizer aminohydrolase, astrocytoma, breast neoplasm, clinical trial, combination chemotherapy, combination therapy, head /neck neoplasm, neoplasm /cancer radiation therapy, pharmacokinetics, prostate neoplasm, rectum neoplasm, uterus neoplasm clinical research, flow cytometry, high performance liquid chromatography, human subject, patient oriented research