A team of chemists from Rice University (Houston, TX, USA, has recently demonstrated the viability of DNA-sized ultrashort carbon nanotubes as delivery agents in radioimmunotherapy. ultrashort carbon nanotubes can function as a delivery platform for radionuclides, targeting small tumors and even single leukemia cells, preventing radionuclide leakage en route to the targeted cancer.
Current surgical techniques used to treat cancer are often imprecise, leaving behind cancerous cells and damaging nontarget tissue, and cancers in certain parts of the body are sometimes considered in-operable. Recent findings, the result of interdisciplin-ary research in cancer biology, physics, chemistry, and electrical and computer engineering have led to new developments in the use of nanotubes to eradicate cancer.
Lead researcher Lon Wilson, Professor of Chemistry, and his team developed and tested a process of loading astatine atoms inside short sections of carbon nanotubes. As they are smaller in size than single cells, the nanotubes can provide highly selective injection of drugs into individual cells and even individual cell nuclei.
The carbon surface of the nanotube is easily modified to provide attachment sites for the targeting agent astatine, which releases α-particles via radioactive decay. These particles are approximately 4000-times more massive than the electrons emitted by β-decay (the type of radiation most commonly used to treat cancer). α-particle radiation can destroy cancerous cells with just one direct hit from an α-particle on a cell.
“There are no FDA-approved cancer therapies that employ α-particle radiation,” said Wilson, “Approved therapies that use β-particles are not well suited for treating cancer at the single-cell level because it takes thousands of β-particles to kill a lone cell. By contrast, cancer cells can be destroyed with just one direct hit from an α-particle on a cell nucleus.”
Although well-established anticancer agents, the use of radionucliotides in anticancer therapy has previously been limited due to its inability to target tumors and leave healthy cells unaffected.
“The unique combination of low penetrating power and large particle mass make α-particles ideal for targeting cancer at the single-cell level,” Wilson said. “The difficulty in developing ways to use them to treat cancer has come in finding ways to deliver them quickly and directly to the cancer site.”
One hurdle in the race to translate any astatine-based cancer therapy into the clinic will be the element’s brief 7.5-h half-life; treatments must be delivered before the particles lose their potency. Furthermore, carbon nanotube treatments that retain the nanotube and nanoparticles intact may result in accumulation of particles and cell debris, causing potential blockages in blood vessels and kidneys, resulting in cytotoxicity.
Source: Hartman KB, Hamlin DK, Wilbur DS, Wilson LJ. 211AtCl@US-tube nanocapsules: a new concept in radiotherapeutic-agent design. Small 3(9), 1496–1499 (2007).
Combination of radiation and drugs most effective in treating lung cancer
A new study reported in Clinical Cancer Research has revealed that the combination of radiation therapy with a drug that destroys the blood vessels feeding malignant tumors is more effective in treating cancer than either treatment alone. Researchers at the UT Southwestern Medical Center, USA, implanted human lung cancer cells into mice to investigate the efficiency of the two treatments combined.
Philip Thorpe, Professor of Pharmacology, and his colleagues have shown that radiation therapy exposes anionic phospholipid membrane components of the endothelial cells that line the blood vessels that nourish tumors.
Thorpe’s earlier research demonstrated the presence of anionic phospholipids, particularly phosphatidylserine, that normally face the cell interior on tumor endothelial cells, indicating that they have been flipped inside out.
“The flipping is likely due to stress conditions present in the tumor microenvironment, and radiation increases the number of exposed phospholipids,” Thorpe commented.
In their study, the investigators looked at nude mice bearing human lung tumors. The researchers found that focal irradiation of the human lung cancer xenografts increased the percentage of exposed phospholipids from 4 to 26%. The mice were also treated with bavituximab, a chimeric antiphosphatidylserine monoclonal antibody that binds selectively to exposed phospholipids on tumor vessels, which signals white blood cells to destroy the vessels nourishing the tumor.
Treating the mice with both radiation therapy and bavituximab reduced blood vessel density and enhanced monocyte infiltration into the tumor mass beyond that observed with either treatment alone. Researchers reported that the combination therapy reduced tumor growth by 80%, a strategy much more effective than administration of either therapy alone (p < 0.01).
“About 30% of all lung cancer patients receive radiation and, in this animal model of lung cancer, we found that this monoclonal antibody improves the efficacy of radiation therapy without the toxicity seen in other chemotherapeutic drugs,” said Thorpe. “It’s a win–win.”
Bavituximab, which was created in Thorpe’s laboratory, is currently being tested on cancer patients in clinical trials in the USA and India for its effectiveness. Peregrine Pharmaceuticals, Inc. has exclusively licensed the antibody from UT Southwestern with a sponsored research agreement to further develop the drug; its use in treating viral infections and other forms of cancer is being explored.
Vascular targeting agents, such as bavituximab, are said to kill tumors without causing damage to surrounding healthy cells, thereby causing fewer adverse effects than conventional therapies that destroy rapidly dividing normal cells along with the cancer cells.
Lung cancer is the leading cause of cancer deaths globally, with more than 1 million cases diagnosed each year. Although there are current therapies, the 5-year survival rate for lung cancer patients remains at only 15%, according to the National Cancer Institute. “This tells us that there is an urgent need to develop new treatment strategies,” Thorpe said.
“The present study suggests that clinical evaluation of bavituximab in combination with radiation therapy should be considered for lung cancer patients and patients with other cancers commonly treated with radiation therapy,” the researchers conclude. It is expected that new clinical trials using a combination of bavituximab and radiotherapy will commence soon.
Source: He J, Luster TA, Thorpe PE. Radiation-enhanced vascular targeting of human lung cancers in mice with a monoclonal antibody that binds anionic phospholipids. Clin. Cancer Res. 13(17), 5211–5218 (2007).
Designer adenovirus kills aggressive brain tumor stem cells
A team of researchers from The University of Texas MD Anderson Cancer Center, Texas, USA, have developed a tailored virus that destroys glioblastoma multiforme stem cells, the most aggressive form of brain tumor, which is highly resistant to radiation and chemotherapy, and commonly inoperable owing to its invasive nature.
Senior researcher Juan Fueyo developed the oncolytic adenovirus, Delta-24-RGD, to target the molecular weakness in tumors while rendering it incapable of replicating in noncancerous tissue. “We have shown first in lab experiments and then in stem cell–derived human brain cancer in mice, that we have a tool that can target and eliminate the cells that drive brain tumors,” Fueyo said.
In a study published in a 2003 issue of Journal of the National Cancer Institute, Fueyo and colleagues demonstrated the ability of Delta-24-RGD to eliminate brain tumors in mice. Brain tumor cells are missing or defective in a protein called retinoblastoma (Rb), which normally guards against both the proliferation of cancerous cells and viral infection. The virus is therefore able to invade and replicate in cancerous cells more easily than healthy tissue, inducing autophagic cell death. Adenoviruses attacking normal cells synthesise a protein, E1A, to counteract Rb. The gene coding for E1A was deleted by Fueyo and colleagues to prevent invasion of Delta-24-RGD in healthy, noncancerous tissue. The modified virus eliminated brain tumors in 60% of mice who received injections directly into their tumors.
Since 2004, research has shown that brain tumors form as a result of stem cells that over-replicate themselves, differentiate into other types of cells and bear protein markers, such as normal stem cells. Fueyo says that these cancer cells, which are the origin of the tumor, are able to resist chemotherapy and radiation administered to patients, and that they drive the renewed growth of the tumor after surgery. “We decided to test Delta-24-RGD against glioma stem cells and tumors grown from them,” he said.
In the study, reported in the September edition of the Journal of the National Cancer Institute, four brain tumor stem cell lines were derived from four specimins of glioblastoma multiforme, all exhibiting the characteristics and protein signatures of stem cells. In laboratory tests, Delta-24-RGD was successful in killing all four cell lines. Stem cell lines were grafted into mice brains and resulting tumors were treated with Delta-24-RGD injections.
Although the round, self-contained tumors in mouse models commonly differ in morphology from their human counterparts, which are more invasive and irregularly shaped, the study found encouraging results. The cancer stem cell-derived tumors demonstrated the characteristics of malignant tumors found in patients.
“We have to be cautious, because an animal model doesn’t fully represent humans, but the tumors grown by these stem cells closely resemble the tumors we see in our patients, which is an exciting finding in itself,” said Fueyo.
Untreated mice had a mean survival time of 38.5 days, while treated mice had a mean survival of 66 days. Of the eight treated mice, two survived for 92 days, until the end of the experiment, with no neurological symptoms.
“It’s important in animal models to see improvement in survival in the majority of animals, but to have some be cured and survive a long time without neurological symptoms is very rare,” said Fueyo.
A clinical quality version of Delta-24-RGD has been manufactured by the National Cancer Institute and Phase I clinical trails are expected to commence shortly.
Source: Jiang H, Gomez-Manzano C, Aoki H et al. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J. Natl Cancer Inst. 95(9), 652–660 (2007).
Drugs developed to fight HIV block tumor growth
Several protease-inhibiting anti-HIV drugs have been found to significantly reduce the growth of cancer cells and increase cell death, according to researchers at the US National Cancer Institute in Bethesda, MD.
Phillip Dennis and his team at the US National Cancer Institute found that three of six protease inhibitors, nelfinavir (Viracept®), ritonavir (Norvir®) and saquinavir (Invirase®), inhibited proliferation of non-small-cell lung carcinoma (NSCLC) cells and every other cancer cell type tested in doses previously proven to be safe in HIV-infected patients. Nelfinavir was found to be most potent, causing cell death by autophagy, induction of endoplasmic reticulum stress and apoptosis. Nelfinavir inhibited the growth of both drug-sensitive and drug-resistant breast cancer cells, indicating that it could be used to fight cancer cells that are resistant to common chemotherapy drugs. There is also evidence to suggest that Nelfinavir may be able to overcome resistance to radiation, the researchers reported.
Ian Hampson from the University of Manchester, UK, who has previously found that lopinavir, another HIV drug, has potential for retarding growth of the human papillomavirus that causes cervical cancer, comments that the results are unsurprising: “Cancers have many parallels to viral infection.”
The strategy of finding new uses for existing drugs is gaining ground, with drug repositioning complementing new drug development. “This could be a new approach to finding cancer drugs and cut the time for getting them approved,” said senior investigator Phillip A Dennis. “Repositioning drugs that are already FDA-approved could accelerate the development of new cancer therapies.”
Preliminary clinical trials have been instigated in patients with a range of cancers, which should reveal the dose that can be tolerated and how it affects solid tumors in the body. The Phase I trial has been initiated to find the most effective dose with the fewest harmful side effects.
“If Nelfinavir is proven effective in fighting cancer, it would, most likely, be used in combination with other cancer drugs,” Dennis said.
Source: Gills JJ, LoPiccolo J, Tsurutani J et al. Nelfinavir, a lead HIV protease inhibitor, is a broad spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin. Cancer Res. 13(13), 5183–5194 (2007).
Vitamin C impedes growth of tumors
As famously proposed by Nobel Prize winner Linus Pauling almost 30 years ago, investigators from John Hopkins University in Baltimore, USA, found that vitamin C impedes tumor growth in mice, but by mechanisms different from those suggested originally.
Previous research had suggested that vitamin C may help to prevent cancer growth as a result of its antioxidant action by preventing DNA damage and genomic instability mediated by volatile oxygen free radicals. However, the Hopkins team, led by Chi Dang, Professor of Medicine and Oncology and Johns Hopkins Family Professor in Oncology Research, unexpectedly found that the antioxidants’ actual role may be to destabilize a tumor’s ability to grow under oxygen-starved conditions.
Investigators report that antioxidants inhibited three tumorigenic models of mice implanted with either human B-cell lymphoma or human liver cancer cells. Both cancers produce high levels of free radicals that can be suppressed by administering the mice two antioxidant supplements: N-acetylcysteine (NAC) and vitamin C.
However, the examination of cancerous cells from cancer-implanted mice that were not fed the antioxidants found them to be absent from significant DNA damage. “Clearly, if DNA damage was not in play as a cause of the cancer, then whatever the antioxidants were doing to help was also not related to DNA damage,” says Ping Gao, senior investigator.
The researchers found that hypoxia-induced factor (HIF)-1, a protein that is switched on when cells run low on oxygen, was absent in cancer cells treated with vitamin C and abundant in untreated cells. HIF-1 is critical for the survival of certain rapidly growing tumors, which require large amounts of oxygen and can only function with a supply of free radicals. Removal of free radicals by antioxidants can therefore suppress HIF-1 action and prevent tumor growth.
“When a cell lacks oxygen, HIF-1 helps it compensate,” explained Dang. “HIF-1 helps an oxygen-starved cell convert sugar to energy without using oxygen and also initiates the construction of new blood vessels to bring in a fresh oxygen supply.”
Findings provide significant support for the antitumorigenic effects of diminishing HIF levels and show great potential for the development of future cancer therapeutics.
“The potential anticancer benefits of antioxidants have been the driving force for many clinical and preclinical studies,” says Dang. “By uncovering the mechanism behind antioxidants, we are now better suited to maximize their therapeutic use.”
Source: Gao P, Zhang H, Dinawahi R et al. HIF-dependant antitumorigenic effects of anti-oxidants in vivo. Cancer Cell 12, 230–238 (2007).