Combination therapy with SCH58500 (p53 adenovirus) and cyclophosphamide in preclinical cancer models.
SCH58500 (ACN53) is a replication-deficient, recombinant adenovirus which expresses human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and it has enhanced activity in combination with many chemotherapeutic drugs. However, the anti-tumor efficacy of SCH58500 combined with the DNA-damaging chemotherapeutic cyclophosphamide has not been previously reported. Cyclophosphamide did not enhance the activity of SCH58500 in three out of four human tumor xenograft models studied. Furthermore, combination therapy with SCH58500 and cyclophosphamide was not any better than single drug treatment in transgenic H-ras mice and in FVB mice bearing syngeneic MidT2-1 tumors. This is in sharp contrast to previous combination studies in these models where SCH58500 had enhanced efficacy when given with the farnesyl protein transferase inhibitor SCH66336, paclitaxel, cisplatin, cisplatin/paclitaxel, or doxorubicin. Further evaluation of this combination is required before it can be recommended for clinical trials in cancer patients.
Nielsen
L L
LL
Tumor Biology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. loretta.nielsen@spcorp.com
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D016159:Tumor Suppressor Protein p53; D003520:Cyclophosphamide