Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation.
OBJECTIVE
To extend our findings in previous radiation and biochemical studies with five rodent tumors, in which we used one and occasionally two or three irradiations. The extent of control of the EMT-6 mammary adenocarcinoma was determined using fractionated radiation (12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2'-deoxycytidine (CldC) and biomodulators of its metabolism: N-(Phosphonacetyl)-L-aspartate (PALA), tetrahydrouridine and 5-fluoro-2'-deoxycytidine (FdC).


METHODS
Mammary adenocarcinoma EMT-6 tumors implanted 1 week prior to therapy in BALB/c mice were subjected to single daily doses of focused radiation, not exceeding a total of 60 Gy, on days 2-5 of each week. N-(Phosphonacetyl)-L-aspartate (PALA) was administered on the first day of therapy. Five-fluoro-2'-deoxycytidine and CldC were administered in the morning and afternoon, respectively, of the next 2 days, and CldC was administered on the fourth day. Tetrahydrouridine was always coadministered with FdC or CldC. Drug and radiation treatments overlapped for 3 weeks.


RESULTS
Fifty to 80% cures (usually 70%) were obtained with no apparent morbidity and the same moderate weight loss that occurs with radiation alone. Neither tumor regrowth delay nor cures were obtained with drugs or radiation alone. An apparent threefold dose increase effect was obtained with the end point: "days to reach 4 times initial tumor volume." Increasing the radiation dose threefold (without drugs) resulted in four out of five deaths; increasing the dose twofold (without drugs) resulted in extensive weight loss and hair loss in the entire ventral area and no cures. Increasing the dose of drugs or radiation 1.5-fold, in the complete protocol, did not result in increased morbidity. Comparative studies with Iododeoxyuridine demonstrate the heightened efficacy of CldC.


CONCLUSIONS
One cannot achieve the same results obtained with CldC and the modulators by merely increasing the dose of radiation. There is a significant window of safety in this approach. The evidence we have obtained with EMT-6, the fifth rodent tumor we have studied with CldC, as well as the demonstrated and proposed reasons for its superior efficacy over 5-Iododeoxyuridine (and 5-Bromodeoxyuridine), drugs in current use, indicate that CldC will allow more aggressive treatment of human tumors with radiation than is now feasible.
Greer
S
S
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Schwade
J
J
Marion
H S
HS
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy*; D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007065:Idoxuridine / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D013767:Tetrahydrouridine / Q000008:administration & dosage
D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D001224:Aspartic Acid; C035826:5-chloro-2'-deoxycytidine; C013195:sparfosic acid; C007746:5-fluoro-2'-deoxycytidine; D007065:Idoxuridine; D010746:Phosphonoacetic Acid