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Anti-vascular targeting: a novel approach to cancer treatment
update
news
PSTT Vol. 3, No. 1 January 2000
Anti-vascular targeting: a novel approach to cancer treatment Anya Hillery, Julio Lopez 5, 2C, Madrid, E-28002, Spain, tel: 134 91 5196847, e-mail: [email protected]
Anti-tumour vascular targeting agents are an entirely new drug class in cancer therapy. Instead of attacking malignant cells directly, these agents are aimed at attacking a tumour’s blood supply, thereby depriving the tumour of the vital oxygen and nutrients necessary for its growth and survival. The first drug of this new class, Combretastatin A4 Prodrug (CA4P), derived from African Bush Willow, has been developed by OXiGENE (Boston, MA, USA) and The Cancer Research Campaign. The prodrug is transformed to the active moiety, Combretastatin A4 (CA4), specifically at the tumour vasculature. CA4 subsequently distorts the endothelial cells lining the vasculature, so that blood-flow to the tumour is significantly reduced. Preclinical studies have shown that this induces ischaemic necrosis of the tumour1. When used in combination with either chemotherapy or radiation, the tumour shrinks and is ultimately completely destroyed. The anti-vascular targeting agents differ from angiogenic inhibitors, another class of drugs currently in clinical trials, also aimed at reducing a tumour’s life-supply. Angiogenic inhibitors aim to prevent the formation of new tumour-specific blood vessels, but they have no effect on pre-existing vasculature; thus, they merely suppress further tumour growth. In contrast, the anti-vascular agents attack pre-existing blood vessels, thereby reducing the tumour. Tumour vasculature targeting and attack In order to effect selective targeting to the tumour vasculature, CA4 is administered as CA4P, the disodium phosphate inactive derivative (prodrug) of CA4. The abnormal microenvironment of the tumour vasculature is associated with a significantly amplified level of surface
4
alkaline phosphatase activity; allowing the conversion of CA4P to occur specifically in the region of the tumour. CA4 is thus liberated to act on the endothelial cells which line the tumour vasculature. CA4 demonstrates potent tubulin-binding activity. Tubulin-binding by CA4 drastically distorts the normal endothelial cell-shape, from thin, flat, and plate-like, to large, rounded and more condensed. These cells ‘balloon’ outwards, constricting blood vessels and reducing blood-flow to the tumour. CA4 also increases the permeability of endothelial cells, causing an increase in interstitial fluid pressure, which further inhibits blood-flow through the vessels. Preclinical studies have shown that inhibition of blood-flow is extremely rapid, occurring within minutes of CA4P injection, with almost 100% shut down in central regions typically occurring within one hour. In addition to its antivascular effects, the tubulin-binding activity of CA4 means that it is also a powerful antiangiogenic agent, inhibiting the proliferation of new, tumour-specific endothelial cells. ‘Inside-out’ tumour killing CA4 preferentially damages central tumour vessels which are already hypoxic and thus more susceptible to the shut-down effects of the drug on the vasculature. The drug is less effective against cells at the tumour periphery, which can obtain their nourishment from surrounding normal tissue. In contrast to this ‘inside-out’ direction of efficacy, approaches such as chemotherapy, radiation and antibody therapies are more effective in targeting peripheral vascularized regions, but are generally less effective in destroying cells in the core. This raises the potential for a powerful synergy achievable by
the combination of CA4P with other approaches; in fact, this synergy has already been demonstrated in preclinical studies. Clinical trials Preliminary data have recently been reported on a UK Phase I clinical study which examined the weekly infusion of CA4P in 17 patients, all with tumour masses .3 cm. Dose escalation is on-going with no toxic effects observed in patients to date. Furthermore, nuclear magnetic resonance imaging (MRI) scans showed that the drug significantly reduced the blood-flow in all patients evaluated above doses of 52 mg/m2. David Sherris, Chief Operating Officer at OXiGENE, commented: “Although Phase I studies are primarily undertaken to evaluate a drug’s safety, the fact that blood-flow reduction was observed here in man demonstrates the ‘proof of principal’ of this approach, confirming the effects of CA4P shown in animal trials could be successfully transferred to man”. This is the first time in cancer research that a drug has been shown to reduce blood-flow to patient (rather than animal) tumours, an exciting step in cancer therapy. Extrapolating the results from animal studies suggests that the vasculature shut down shown here in patients will subsequently starve the tumours of nutrients and oxygen, causing tumour death. Further clinical trials will be able to explore this possibility. Trials are also planned to evaluate the efficacy in patients of CA4P in combination with other anti-cancer therapies. Reference 1
Chaplin, D.J. et al. (1999) Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 19, 189–195
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00229-1
news
PSTT Vol. 3, No. 1 January 2000
Anti-vascular targeting: a novel approach to cancer treatment Anya Hillery, Julio Lopez 5, 2C, Madrid, E-28002, Spain, tel: 134 91 5196847, e-mail: [email protected]
Anti-tumour vascular targeting agents are an entirely new drug class in cancer therapy. Instead of attacking malignant cells directly, these agents are aimed at attacking a tumour’s blood supply, thereby depriving the tumour of the vital oxygen and nutrients necessary for its growth and survival. The first drug of this new class, Combretastatin A4 Prodrug (CA4P), derived from African Bush Willow, has been developed by OXiGENE (Boston, MA, USA) and The Cancer Research Campaign. The prodrug is transformed to the active moiety, Combretastatin A4 (CA4), specifically at the tumour vasculature. CA4 subsequently distorts the endothelial cells lining the vasculature, so that blood-flow to the tumour is significantly reduced. Preclinical studies have shown that this induces ischaemic necrosis of the tumour1. When used in combination with either chemotherapy or radiation, the tumour shrinks and is ultimately completely destroyed. The anti-vascular targeting agents differ from angiogenic inhibitors, another class of drugs currently in clinical trials, also aimed at reducing a tumour’s life-supply. Angiogenic inhibitors aim to prevent the formation of new tumour-specific blood vessels, but they have no effect on pre-existing vasculature; thus, they merely suppress further tumour growth. In contrast, the anti-vascular agents attack pre-existing blood vessels, thereby reducing the tumour. Tumour vasculature targeting and attack In order to effect selective targeting to the tumour vasculature, CA4 is administered as CA4P, the disodium phosphate inactive derivative (prodrug) of CA4. The abnormal microenvironment of the tumour vasculature is associated with a significantly amplified level of surface
4
alkaline phosphatase activity; allowing the conversion of CA4P to occur specifically in the region of the tumour. CA4 is thus liberated to act on the endothelial cells which line the tumour vasculature. CA4 demonstrates potent tubulin-binding activity. Tubulin-binding by CA4 drastically distorts the normal endothelial cell-shape, from thin, flat, and plate-like, to large, rounded and more condensed. These cells ‘balloon’ outwards, constricting blood vessels and reducing blood-flow to the tumour. CA4 also increases the permeability of endothelial cells, causing an increase in interstitial fluid pressure, which further inhibits blood-flow through the vessels. Preclinical studies have shown that inhibition of blood-flow is extremely rapid, occurring within minutes of CA4P injection, with almost 100% shut down in central regions typically occurring within one hour. In addition to its antivascular effects, the tubulin-binding activity of CA4 means that it is also a powerful antiangiogenic agent, inhibiting the proliferation of new, tumour-specific endothelial cells. ‘Inside-out’ tumour killing CA4 preferentially damages central tumour vessels which are already hypoxic and thus more susceptible to the shut-down effects of the drug on the vasculature. The drug is less effective against cells at the tumour periphery, which can obtain their nourishment from surrounding normal tissue. In contrast to this ‘inside-out’ direction of efficacy, approaches such as chemotherapy, radiation and antibody therapies are more effective in targeting peripheral vascularized regions, but are generally less effective in destroying cells in the core. This raises the potential for a powerful synergy achievable by
the combination of CA4P with other approaches; in fact, this synergy has already been demonstrated in preclinical studies. Clinical trials Preliminary data have recently been reported on a UK Phase I clinical study which examined the weekly infusion of CA4P in 17 patients, all with tumour masses .3 cm. Dose escalation is on-going with no toxic effects observed in patients to date. Furthermore, nuclear magnetic resonance imaging (MRI) scans showed that the drug significantly reduced the blood-flow in all patients evaluated above doses of 52 mg/m2. David Sherris, Chief Operating Officer at OXiGENE, commented: “Although Phase I studies are primarily undertaken to evaluate a drug’s safety, the fact that blood-flow reduction was observed here in man demonstrates the ‘proof of principal’ of this approach, confirming the effects of CA4P shown in animal trials could be successfully transferred to man”. This is the first time in cancer research that a drug has been shown to reduce blood-flow to patient (rather than animal) tumours, an exciting step in cancer therapy. Extrapolating the results from animal studies suggests that the vasculature shut down shown here in patients will subsequently starve the tumours of nutrients and oxygen, causing tumour death. Further clinical trials will be able to explore this possibility. Trials are also planned to evaluate the efficacy in patients of CA4P in combination with other anti-cancer therapies. Reference 1
Chaplin, D.J. et al. (1999) Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 19, 189–195
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00229-1