3-deazauridine and cyclopentenyl-cytosine

3-Deazauridine (DAUrd), a competitive inhibitor of CTP synthetase, inhibits both RNA and DNA synthesis. Murine leukemia cells resistant to cytosine arabinoside (ara-C) due to a deletion of deoxycytidine kinase are collaterally sensitive to DAUrd, which inhibits the de novo production of CTP and hence results in dCTP depletion. We evaluated DAUrd in combination with the palmitate derivative of ara-C (palmO-ara-C) in mice bearing L1210 leukemia cells with a subpopulation resistant to ara-C. Both simultaneous administration and a sequential schedule of palmO-ara-C at its maximally tolerated dose (MTD), followed by DAUrd treatment, failed to produce a therapeutic gain. We also studied whether non-toxic doses of DAUrd (15-250 mg/kg i.p. at h 0 and 6 on days 4 and 8) could modulate the antileukemic activity of palmO-ara-C (7.5-120 mg/kg i.p. at h 3 on days 4 and 8). The addition of DAUrd produced a modest (but statistically significant) prolongation of life span and a further 2-log10 reduction in tumor burden compared to the same dose of palmO-ara-C alone, and resulted in long-term survivors in five of 30 treated animals. Two-dimensional dose-response analysis of the survival data indicated a positive drug interaction (p less than or equal to 0.01) when the dosage of DAUrd was modeled to reflect an apparent threshold effect. Cyclopentenyl cytosine (CPE-C; 0.625-2.5 mg/kg i.p. at h 0 and 6 on days 4 and 8), a more potent inhibitor of CTP synthetase, was also given with palmO-ara-C. This combination resulted in an additional 2-6 log10 units of cell kill and occasional long-term survivors at palmO-ara-C dosages that alone resulted in no more than 2 log10 units of cell kill and no long-term survivors. However, DAUrd and CPE-C given with palmO-ara-C increased host toxicity, compromising the tolerable dose of palmO-ara-C. Single-agent palmO-ara-C given at its MTD produced a similar reduction in tumor burden and increase in life span compared to the highest palmO-ara-C dose that could be given in combination with either modulator.

Topics: 3-Deazauridine; Animals; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Cytidine; Drug Resistance; Drug Synergism; Female; Leukemia L1210; Male; Mice; Mice, Inbred Strains; Remission Induction; Survival Rate

Cyclopentenylcytosine (CPE-C, 2), a pyrimidine analogue of the fermentation derived carbocyclic nucleoside neplanocin A, has been synthesized from the optically active cyclopentenylamine 3b by two synthetic routes. CPE-C demonstrates significant antitumor activity against both the sensitive and ara-C resistant lines of L1210 leukemia in vivo. Multiple long term survivors are produced in both tumor models. The compound also gives 100% growth inhibition of the solid human A549 lung and MX-1 mammary tumor xenografts grown in athymic mice. Good activity is also observed against a third human tumor xenograft model, metastatic LOX melanoma. CPE-C has significant activity against both DNA and RNA viruses in vitro. Potent activity is observed against HSV-1 (TK+ and TK-), HSV-2, vaccinia, cytomegalovirus, and varicella-zoster virus. Good activity is also found against a strain of influenza virus (Hong Kong flu), vesicular stomatitis virus, Japanese encephalitis virus, and Punta Toro virus.

Topics: 3-Deazauridine; Animals; Antineoplastic Agents; Antiviral Agents; Chemical Phenomena; Chemistry; Cytidine; DNA Viruses; Humans; Leukemia L1210; Leukemia P388; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Orthomyxoviridae; RNA Viruses; Sarcoma, Experimental; Viruses