PMID- 19318483
OWN - NLM
STAT- MEDLINE
DCOM- 20091022
LR  - 20131121
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 7
DP  - 2009 Apr 1
TI  - Cytosine deaminase-uracil phosphoribosyltransferase and interleukin (IL)-12 and 
      IL-18: a multimodal anticancer interface marked by specific modulation in serum 
      cytokines.
PG  - 2323-34
LID - 10.1158/1078-0432.CCR-08-2039 [doi]
AB  - PURPOSE: To test the effects of a new combination, cytosine deaminase (CD) + 
      uracil phosphoribosyltransferase (UPRT)-mediated gene-directed enzyme prodrug 
      therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine 
      prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 
      1/Th2 serum cytokine balance with a special focus to assess correlation with 
      tumor burden/survival. EXPERIMENTAL DESIGN: Efficacy of intraprostatic 
      administration of adenovirally delivered murine IL-12 and IL-18 against 
      orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At 
      necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, 
      vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + 
      cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate 
      tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were 
      also assessed. Host immune responses to different treatments were assessed by 
      monitoring 11 serum cytokines using Luminex technology. RESULTS: Our data show 
      that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant 
      reduction in local RM1 tumors and lung colonies with enhanced long-term survival 
      versus individual treatments. A dramatic enhancement of tumor infiltration by a 
      wider repertoire of immune cells and disruption of vasculature implied the 
      combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering 
      of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently 
      associated with lower tumor burden (local and systemic), and this, rather than an 
      increase in Th1 cytokines, better predicted treatment efficacy. In addition, 
      mouse survival correlated with substantially higher cytokine (Th1/Th2) levels 
      after treatment. CONCLUSION: Locoregional application of CDUPRT-GDEPT and 
      IL-12/IL-18 was effective against local and systemic prostate cancer and improved 
      survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor 
      burden and, hence, host response to therapy.
FAU - Khatri, Aparajita
AU  - Khatri A
AD  - Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales, 
      Australia. a.khatri@unsw.edu.au
FAU - Husaini, Yasmin
AU  - Husaini Y
FAU - Ow, Kim
AU  - Ow K
FAU - Chapman, Jane
AU  - Chapman J
FAU - Russell, Pamela J
AU  - Russell PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20090324
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-18)
RN  - 0 (Prodrugs)
RN  - 187348-17-0 (Interleukin-12)
RN  - D83282DT06 (Flucytosine)
RN  - EC 2.4.2.- (Pentosyltransferases)
RN  - EC 2.4.2.9 (uracil phosphoribosyltransferase)
RN  - EC 3.5.4.1 (Cytosine Deaminase)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Combined Modality Therapy
MH  - Cytokines/*blood
MH  - Cytosine Deaminase/*genetics
MH  - Flucytosine/therapeutic use
MH  - Interleukin-12/*genetics
MH  - Interleukin-18/*genetics
MH  - Lung Neoplasms/secondary
MH  - Lymphocytes, Tumor-Infiltrating/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pentosyltransferases/*genetics
MH  - Prodrugs/therapeutic use
MH  - Prostatic Neoplasms/immunology/pathology/*therapy
MH  - Survival Analysis
MH  - Th2 Cells/immunology
EDAT- 2009/03/26 09:00
MHDA- 2009/10/23 06:00
CRDT- 2009/03/26 09:00
PHST- 2009/03/26 09:00 [entrez]
PHST- 2009/03/26 09:00 [pubmed]
PHST- 2009/10/23 06:00 [medline]
AID - 1078-0432.CCR-08-2039 [pii]
AID - 10.1158/1078-0432.CCR-08-2039 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Apr 1;15(7):2323-34. doi: 10.1158/1078-0432.CCR-08-2039. 
      Epub 2009 Mar 24.