Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models.
BACKGROUND
Photodynamic therapy (PDT) is a promising therapeutic modality using a tumor localizing photosensitizer and light to destroy tumor cells. A major limitation of PDT is tumor recurrence, which is partly due to neovascularization.


OBJECTIVE
The objective of the present study was to determine whether combination therapy with PDT and antiangiogenic agents (i.e. SU5416 and SU6668) would be more effective in controlling tumor recurrence in a mouse model of human CNE2 poorly differentiated nasopharyngeal carcinoma compared with PDT or antiangiogenic agents administered alone.


METHODS
Athymic mice bearing CNE2 tumor xenografts received daily i.p. injections of 20 mg/kg SU5416 or 100 mg/kg SU6668 for 28 consecutive days either alone or following a single hypericin-PDT treatment.


RESULTS
Significant inhibition of CNE2 tumor growth was observed in all treatment groups. Differences in 4x tumor growth time, the number of mice with 4x tumor growth, tumor growth inhibition as well as the percent of mice surviving were not statistically significant among individual treatment groups. However, the number of mice with 4x tumor growth observed in SU6668 monotherapy and combined PDT and SU6668 treatment groups was significantly less than that in the control group (P<0.05 and 0.01, respectively). Moreover, compared with the control group, only the combined PDT and SU6668 treatment significantly extended survival of tumor-bearing host mice (P<0.05). The semiquantitative RT-PCR results showed that the expression of HIF-1alpha, VEGF, COX-2 and bFGF were increased in PDT-treated tumor samples collected 24 h post-PDT, suggesting that PDT-induced damage to tumor microvasculature and the resultant hypoxia upregulate the expression of certain proangiogenic factors.


CONCLUSIONS
The effectiveness of PDT can be enhanced by antiangiogenic treatment with the synthetic RTK inhibitors. Of the two synthetic RTK inhibitors tested, SU6668 was more effective than SU5416 in enhancing tumor responsiveness to PDT.
Laboratory of Clinical Pharmacology Division of Clinical Trials & Epidemiological Sciences, National Cancer Centre, 11, Hospital Drive, 169610, Singapore.
Qingyu
Q
Zhou
Malini
M
Olivo
Karen Yee Kar
KY
Lye
Shirley
S
Moore
Amarnath
A
Sharma
Balram
B
Chowbay
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000873:Anthracenes; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000078183:Oxindoles; D010569:Perylene / Q000031:analogs & derivatives / Q000627:therapeutic use; D010778:Photochemotherapy; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D015996:Survival Rate
D020533:Angiogenesis Inhibitors; D000873:Anthracenes; D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011506:Proteins; D011758:Pyrroles; D010569:Perylene; C116890:Semaxinib; C004965:hypericin; C412603:orantinib; D011505:Protein-Tyrosine Kinases