Novel combination therapy for human colon cancer with adenovirus‐mediated wild‐type p53 gene transfer and DNA‐damaging chemotherapeutic agent

Abstract

Alteration of the wild-type (wt) p53 gene by mutation, deletion or re-arrangement is a major factor in the development of human colon cancer. Recent studies have demonstrated that p53 might be an essential component of the apoptotic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the anti-tumor effects of adenovirus-mediated wt-p53 gene transfer in combination with a chemotherapeutic drug on the human colon cancer cell line WiDr, which is homozygous for a mutation in the p53 gene. Treatment with the chemotherapeutic drug cisplatin following infection with a replication-deficient, recombinant adenoviral vector expressing wt-p53 (termed AdCMVp53) significantly suppressed the growth of WiDr cells compared to single treatments alone. To evaluate the in vivo efficacy of AdCMVp53 and cisplatin given sequentially, WiDr cells were inoculated s.c. in nu/nu mice. After 3 days, AdCMVp53 was injected s.c. into the area where tumor cells were implanted, followed by i.p. administration of cisplatin. Analysis of initial growth inhibition at 21 days demonstrated a profound therapeutic cooperativity, though administration of either AdCMVp53 or cisplatin alone was followed only by a slowing of growth. Our results suggest that gene therapy using wt-p53-expressing adenovirus in combination with a chemotherapeutic DNA-damaging drug could be a useful strategy for treating human colon cancer. Int.

Downmodulation of bFGF-binding protein expression following restoration of p53 function

“…At most, the circulating Av1p53 could have directly infected 5-10% of the cells in this tumor. 37,47,55,60,72,73 To result in the complete elimination of the bFGF -BP signal we observed, every cell, theoretically, must have the gene downregulated. It is conceivable that by regulating the expression of another secreted intermediate (or more than one ), bFGF -BP expression was down -regulated in our system.…”

“…71,72 Wtp53 -mediated tumor growth inhibition is a complex process. These findings have demonstrated that wtp53 -induced tumor regression may be due, at least in part, to antiangiogenesis mediated through the downmodulation of bFGF -BP.…”

Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

“…[34][35][36] Infection of p53 family gene adenovirus alone did not induce apoptosis in SW480 cells. In contrast, here we performed adenoviral infection in combination with adriamycin or X-radiation and noted induction of apoptosis.…”

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

“…Additionally, Ad-MMAC infection of UM-UC-6dox cells showed a synergistic e ect with doxorubicin in causing cytotoxicity. Other forms of gene therapy, for example p53, have been shown to modulate sensitivity to DNA-damaging drugs, especially cisplatin (Fujiwara et al, 1994;Ogawa et al, 1997;Gurnani et al, 1999). However, the mechanisms of this phenomenon are unknown.…”