Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agents.
Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that C. novyi-NT in combination with anti-microtubule agents can cause the destruction of both the vascular and avascular compartments of tumors. The two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with C. novyi-NT. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by C. novyi-NT. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which C. novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity.
Dang
Long H
LH
Howard Hughes Medical Institute and Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Bettegowda
Chetan
C
Agrawal
Nishant
N
Cheong
Ian
I
Huso
David
D
Frost
Philip
P
Loganzo
Frank
F
Greenberger
Lee
L
Barkoczy
Jozsef
J
Pettit
George R
GR
Smith
Amos B
AB
Gurulingappa
Hallur
H
Khan
Saeed
S
Parmigiani
Giovanni
G
Kinzler
Kenneth W
KW
Zhou
Shibin
S
Vogelstein
Bert
B
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D003013:Clostridium / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism*; D009336:Necrosis; D009369:Neoplasms / Q000628:therapy; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000494:pharmacology; D012039:Regional Blood Flow; D013170:Spores; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D001427:Bacterial Toxins; C075216:Clostridium novyi alpha-toxin; C473896:HTI-286; D009842:Oligopeptides; D014747:Vinblastine; D000077235:Vinorelbine