The management of breast cancer in women under the age of 40 continues to challenge oncologists despite many recent therapeutic advances. The higher rates of breast cancer recurrence and death in this cohort strongly correlate with unfavorable clinicopathologic features. The author is to be complimented on a comprehensive overview of breast cancer management in young women. In this review, we discuss pregnancy following a diagnosis of breast cancer, fertility concerns related to treatment, and the potentially life-threatening complications cardiotoxicity and leukemogenesis.
Pregnancy-Associated Breast CancerPregnancy-associated breast cancer, which is defined as breast cancer developing during or within 1 year after pregnancy, complicates approximately 0.2% to 3.8% of pregnancies.[1] More specifically, 10% of women under 40 with breast cancer develop the disease while pregnant.[2] Those women with pregnancy-associated breast cancer appear to have more advanced disease at diagnosis when compared to a control population, which may be partly explained by delays in diagnosis.[3] Pathologic evaluation is more likely to reveal a poorly differentiated tumor with a higher proportion of hormone receptor negativity.[4] Contrary to prior opinion, the prognosis for patients with pregnancy-associated breast cancer appears similar when compared to age- and stage-matched nonpregnant controls.[5]
Therapy During PregnancyCurative surgery in the third trimester is recommended as there is no known increased fetal risk related to anesthesia. Breast conservation is an option if appropriate and axillary dissection is preferred over sentinel node mapping due to a lack of safety data to support the latter in this setting.
The indications for systemic chemotherapy for the pregnant patient are similar to those for the nonpregnant patient. In a large prospective trial, 57 pregnant breast cancer patients were treated with FAC (fluorouracil [5-FU], doxorubicin [Adriamycin], and cyclophosphamide) in the second and third trimesters.[6] At a median follow-up of 38.5 months, 40 women remained alive and free from disease; no significant short-term complications detected in those children exposed to chemotherapy in utero. Long-term effects, if any, are yet to be determined.
Only case reports exist for the use of other agents during pregnancy, including the taxanes, vinorelbine, trastuzumab (Herceptin), and lapatinib (Tykerb); their routine use is not recommended until after delivery.[7] However, the choice and timing of chemotherapy largely depends on the clinical situation. Consideration should be given to whether delaying effective therapies will result in a worse outcome for an individual patient. Radiation and hormonal therapy should be deferred until after pregnancy. Finally, reports to date do not indicate that termination of pregnancy results in improved outcome for pregnant breast cancer patients.[2,8]
Pregnancy After Breast Cancer DiagnosisThere is no evidence thus far that pregnancy after a diagnosis of breast cancer is associated with worse long-term maternal survival. On the contrary, certain studies suggest a reduced risk of death in such women vs matched controls.[9,10] Whether there is a biologic explanation for this such as a protective effect of high levels of estrogen or whether it indicates a “healthy mother effect” is unclear. In general women are advised to avoid pregnancy in the first 2 years following a diagnosis of breast cancer, as this period is associated with the highest risk of recurrence. For those with hormone-sensitive disease, this also allows at least 2 years of adjuvant hormonal therapy. However, there is no evidence that this strategy reduces recurrence risk in this population.
Fertility Preservation: Ovarian Suppression vs ChemotherapyAs age is an important feature that helps define risk of recurrence, an aggressive adjuvant chemotherapeutic approach is employed in many young women.[11] The author describes how the aim of therapy in the premenopausal population is to maximize breast cancer outcomes, while minimizing both short- and long-term toxicities.
For those who wish to become pregnant or avoid the effects of premature menopause, chemotherapy-induced amenorrhea is a significant and yet often underdiscussed side effect. In a prospective trial, the rate of menstruation after adjuvant chemotherapy was found to be dependent on age, the chemotherapy administered, and the period of time since treatment. Recovery of menses, a surrogate marker for fertility, occurred in approximately 60% of women receiving AC alone at 1 year of follow-up. Far lower rates of recovery were observed with the addition of a taxane or adjuvant treatment with CMF (cyclophosphamide, methotrexate, and 5-FU).[12] Even temporary cessation of menses after chemotherapy appears to predict earlier onset of menopause.[13]
In light of these findings, the role of ovarian suppression as an adjuvant treatment for premenopausal women with hormone-receptor–positive breast cancer has been investigated as an alternative to chemotherapy. Adjuvant goserelin (Zoladex) alone in this patient population results in recovery of menses in the majority of patients after completion of 2 years of therapy.[14] This and other studies have indicated no survival advantage for CMF over ovarian suppression in both node-positive and node-negative cohorts.[15] The PERCHE (Premenopausal Endocrine Responsive CHEmotherapy) trial planned to investigate the efficacy of modern chemotherapy regimens in addition to ovarian suppression in this population, but unfortunately it was closed due to poor accrual.
Based on the available evidence, ovarian suppression may be offered as an alternative to chemotherapy in young women, in particular where fertility is a concern.
Cardiotoxicity and LeukemogenesisTwo other serious and potentially life-threatening complications briefly mentioned in the article by Peppercorn include cardiotoxicity and leukemogenesis. The incidence of cardiotoxicity after AC (doxorubicin [Adriamycin] and cyclophosphamide), for example, can be as high as 5% to 7%.[16] The addition of trastuzumab to adjuvant regimens can further potentiate anthracycline-induced cardiotoxicity, at times precluding subsequent trastuzumab administration in relevant populations. Future assessment of molecular predictors of response to anthracyclines, such as topoisomerase II expression and administration of equally effective non–anthracycline-containing regimens in the management of early breast cancer, may limit this serious adverse effect.[17,18]
The absolute risk of developing treatment-related acute myeloid leukemia at 10 years after any adjuvant chemotherapy for breast cancer has been shown to be 1.8% vs 1.2% for women who have not received chemotherapy.[19] In a recent population-based study of 420,076 women with a diagnosis of breast cancer, both age < 50 (relative risk [RR] 4.14; P < .001) and stage 3 disease at diagnosis (RR 2.19; P < .001) were associated with an increased risk of AML. It was suggested that these patients may have received more intensive adjuvant regimens or may be more likely to have germline mutations in BRCA1, BRCA2, and other genes involved in DNA repair.
Recent evidence has also suggested that the use of colony-stimulating factors may double the risk of hematologic malignancies among women with early breast cancer.[20] This association needs confirmation, but is thought-provoking when we consider the widespread use of adjuvant “third-generation” anthracycline-based chemotherapy regimens incorporating growth factors.
ConclusionComplex and multidisciplinary treatment planning is often required in young women with early breast cancer because of concerns relating to pregnancy, fertility, long-term toxicities, quality of life, and psychosocial issues. It is imperative that the available evidence is portrayed clearly at initial assessment in order to formulate a treatment plan that will be both safe and acceptable to each individual. Future research should aim to improve on breast cancer outcomes while minimizing toxicity associated with adjuvant therapy.
Saturday, August 22, 2009
Health Tapioca treatment for cancer
For many adults, tapioca is inextricably linked to school dinners Tapioca pudding - widely known as frog's eggs by many school pupils - may after all be good for you.
Scientists say the plant from which it is derived may help cure cancer.
Tapioca is derived from the cassava plant.
It is one of many plants which manufactures cyanide to deter animals who might want to eat it.
It does this by producing a chemical called linamarin which releases hydrogen cyanide when it is broken down by the linamarase enzyme.
Geneticists at Newcastle University have been taking genetic material from the cassava plant and adding it to a virus.
This is then introduced into cancer cells which have been impregnated with linamarin from the cassava plant.
The aim is for the cancer cells to produce hydrogen cyanide in high enough doses so that they commit suicide.
Hydrogen cyanide
Professor Monica Hughes has been studying cassava and cancer for seven years.
She has cloned the genes from the plant which are responsible for producing hydrogen cyanide.
Her objective is to reduce the toxicity of the cyanide so that it will not harm humans.
Cassava is a staple crop for many people in Africa, Asia and South America, but, if it is processing wrongly, it can lead to cyanide poisoning.
Because the plant is rarely used in Western diets, it has not been subject to much scrutiny by geneticists.
Professor Hughes has been working with a research team in Madrid to modify the cassava gene and transfer it to a retrovirus.
This gives the retrovirus the ability to produce linamarase.
The Spanish researchers found that a brain tumour in a rat was totally eradicated after one week of the genetic treatment.
It allowed the localised release of small doses of cyanide through the breakdown of linamarin by linamarase.
Neighbouring cells
The team found that part of the reason the tumour was so quickly destroyed was that the cells containing the retrovirus also affected surrounding cells.
They say tests on human tissue samples for certain cancers also look promising.
Professor Hughes' research has been funded by the European Union, but her funding has now run out and she is looking for other sources.
She says her next step is "to modify the genetic material with a view to making the treatment more effective when applied to mammalian cells".
A spokesman for Newcastle University said the research showed how genetically modifying plants could bring beneficial effects.
Scientists say the plant from which it is derived may help cure cancer.
Tapioca is derived from the cassava plant.
It is one of many plants which manufactures cyanide to deter animals who might want to eat it.
It does this by producing a chemical called linamarin which releases hydrogen cyanide when it is broken down by the linamarase enzyme.
Geneticists at Newcastle University have been taking genetic material from the cassava plant and adding it to a virus.
This is then introduced into cancer cells which have been impregnated with linamarin from the cassava plant.
The aim is for the cancer cells to produce hydrogen cyanide in high enough doses so that they commit suicide.
Hydrogen cyanide
Professor Monica Hughes has been studying cassava and cancer for seven years.
She has cloned the genes from the plant which are responsible for producing hydrogen cyanide.
Her objective is to reduce the toxicity of the cyanide so that it will not harm humans.
Cassava is a staple crop for many people in Africa, Asia and South America, but, if it is processing wrongly, it can lead to cyanide poisoning.
Because the plant is rarely used in Western diets, it has not been subject to much scrutiny by geneticists.
Professor Hughes has been working with a research team in Madrid to modify the cassava gene and transfer it to a retrovirus.
This gives the retrovirus the ability to produce linamarase.
The Spanish researchers found that a brain tumour in a rat was totally eradicated after one week of the genetic treatment.
It allowed the localised release of small doses of cyanide through the breakdown of linamarin by linamarase.
Neighbouring cells
The team found that part of the reason the tumour was so quickly destroyed was that the cells containing the retrovirus also affected surrounding cells.
They say tests on human tissue samples for certain cancers also look promising.
Professor Hughes' research has been funded by the European Union, but her funding has now run out and she is looking for other sources.
She says her next step is "to modify the genetic material with a view to making the treatment more effective when applied to mammalian cells".
A spokesman for Newcastle University said the research showed how genetically modifying plants could bring beneficial effects.
Phase III Trial Initiated for BLP25 Liposome Vaccine in Breast Cancer Patients
Merck KGaA of Darmstadt, Germany, has initiated a global phase III trial of BLP25 liposome vaccine (L-BLP25, Stimuvax) in patients with hormone receptor–positive, locally advanced, recurrent or metastatic breast cancer. L-BLP25 is an investigational therapeutic cancer vaccine being developed by Merck KGaA under a license agreement with Oncothyreon.
The phase III placebo-controlled trial, named STRIDE (STimulating immune Response In aDvanced brEast cancer), is anticipated to enroll more than 900 patients at approximately 180 sites in over 30 countries. The primary endpoint of STRIDE is progressionfree survival. Overall survival, quality of life, tumor response, and safety will also be assessed.
The phase III placebo-controlled trial, named STRIDE (STimulating immune Response In aDvanced brEast cancer), is anticipated to enroll more than 900 patients at approximately 180 sites in over 30 countries. The primary endpoint of STRIDE is progressionfree survival. Overall survival, quality of life, tumor response, and safety will also be assessed.
Pregnancy Hormone HCG Protects Against Breast Cancer Even In Short-term Treatments
ScienceDaily (Apr. 25, 2009) — One of the most effective ways to prevent breast cancer is through a full-term pregnancy at an early age. Studies out of Fox Chase Cancer Center have linked this protective effect to the presence of human chorionic gonadotropin (hCG), a hormone produced by the placenta to maintain the early stages of pregnancy.
Their findings in an animal model of breast cancer showed that rats exposed to hCG over a 21 day period (the length of rat pregnancy), are far less likely to develop breast cancer when exposed to a known carcinogen.
Today, at the 100th Annual Meeting of the American Association for Cancer Research. Johana Vanegas, M.D., a research associate at Fox Chase, presents findings suggesting that even a much shorter exposure to hCG can prevent breast cancer in rats.
Venegas is a member of the laboratory of Jose Russo, M.D. and Irma Russo, M.D., who were the first scientists to propose hCG as an anti-cancer agent. Their studies have shown that hCG offers lasting, protective changes within breast tissue. Clinical trials of hCG in women, based on their work, are currently under way at three locations, nationally, including Fox Chase Cancer Center, and in one European country. The hCG hormone is an FDA-approved agent frequently used for fertility treatments.
"The ability to replicate the naturally protective effects of pregnancy against breast cancer will hold a significant public health value," says Vanegas. "In order to translate our finding into humans, a clinical trial with hCG as a preventive agent against breast cancer, is already ongoing in pre-menopausal women with no previous pregnancy."
Vanegas and her colleagues studied virgin female rats, which had been divided into four groups: a control group, which did not receive hCG, and three groups that received hCG for five, ten or fifteen consecutive days. Following the treatment, each rat received a single dose of a breast cancer-inducing agent.
According to Vanegas, 90.9 percent of the rats in the control group developed breast tumors, compared to 71.4 percent, 57.1 percent, and 15.4 percent in the five, ten and fifteen day-treated animals, respectively. In addition, the average tumor size was also smaller in all the animals that received any of the three hCG treatments.
"The animals that received hCG, but still developed breast cancer did so much later than the control group, which further demonstrates the protective effects of hCG," Vanegas says. "While we don't foresee side effects among humans in using hCG, it is helpful to know that even smaller doses confer benefits on breast tissue."
Funding for this research comes from grants from the National Institutes of Health and the National Cancer Institute.
Their findings in an animal model of breast cancer showed that rats exposed to hCG over a 21 day period (the length of rat pregnancy), are far less likely to develop breast cancer when exposed to a known carcinogen.
Today, at the 100th Annual Meeting of the American Association for Cancer Research. Johana Vanegas, M.D., a research associate at Fox Chase, presents findings suggesting that even a much shorter exposure to hCG can prevent breast cancer in rats.
Venegas is a member of the laboratory of Jose Russo, M.D. and Irma Russo, M.D., who were the first scientists to propose hCG as an anti-cancer agent. Their studies have shown that hCG offers lasting, protective changes within breast tissue. Clinical trials of hCG in women, based on their work, are currently under way at three locations, nationally, including Fox Chase Cancer Center, and in one European country. The hCG hormone is an FDA-approved agent frequently used for fertility treatments.
"The ability to replicate the naturally protective effects of pregnancy against breast cancer will hold a significant public health value," says Vanegas. "In order to translate our finding into humans, a clinical trial with hCG as a preventive agent against breast cancer, is already ongoing in pre-menopausal women with no previous pregnancy."
Vanegas and her colleagues studied virgin female rats, which had been divided into four groups: a control group, which did not receive hCG, and three groups that received hCG for five, ten or fifteen consecutive days. Following the treatment, each rat received a single dose of a breast cancer-inducing agent.
According to Vanegas, 90.9 percent of the rats in the control group developed breast tumors, compared to 71.4 percent, 57.1 percent, and 15.4 percent in the five, ten and fifteen day-treated animals, respectively. In addition, the average tumor size was also smaller in all the animals that received any of the three hCG treatments.
"The animals that received hCG, but still developed breast cancer did so much later than the control group, which further demonstrates the protective effects of hCG," Vanegas says. "While we don't foresee side effects among humans in using hCG, it is helpful to know that even smaller doses confer benefits on breast tissue."
Funding for this research comes from grants from the National Institutes of Health and the National Cancer Institute.
Precious Metal Could Lead To Next Generation Of Cancer Treatments
ScienceDaily (Dec. 10, 2008) — A precious metal which has never before been used in a clinical setting is being developed as an anti-cancer agent by University of Warwick researchers.
The metal, osmium, is closely related to platinum, which is widely used to treat cancers in the form of the drug cisplatin. Most famously, the cyclist Lance Armstrong was treated with cisplatin for testicular cancer.
Now the researchers, based in the Department of Chemistry, at the University of Warwick, are working closely with Warwick Ventures, the university’s technology transfer office, to seek partners to help develop the potential of osmium through more extensive biological tests. The team will be presenting their work on 9 December at the national university technology showcase event, Bioversity.
Professor Peter Sadler, of the Department of Chemistry, explained: “Although cisplatin has been proven to be a very successful treatment; it is not useful for all kinds of cancer. It is also quite a toxic therapy, which can produce side effects and, from a clinical point of view, cells can also become resistant to platinum.”
Osmium, with its special chemical properties, offers a new potential solution to an unmet clinical need. It has shown huge promise in treating several different types of cancer cell, including ovarian and colon cancers which have been developed and tested in the laboratory. The metal also has another advantage in that it is a much cheaper alternative to platinum.
Professor Sadler, along with post-graduate researcher Sabine van Rijt, is working to develop new compounds using Osmium, which they hope will lead to the development of drugs which could be used in combination therapies alongside existing drugs such as cisplatin.
“The compounds we have been developing are very promising,” says Sabine van Rijt. “We’re building a picture of how different compounds might interact with DNA in cancer cells. By making changes to the coating, or ligand, on the metal, we can also affect not just how it interacts, but the rate of interaction. During this design process we can also make changes which can control the activity of the compound.”
She added: “Another advantage is that these compounds are not cross-resistant with platinum. They kill the cancerous cells in a different way, so they could be used alongside platinum in combination therapies.”
The team’s research is being presented on 9 December at Bioversity 2008, a national university technology showcase event. Bioversity is part of the biotechnology conference, Genesis 2008, organised by The London Biotechnology Network.
The metal, osmium, is closely related to platinum, which is widely used to treat cancers in the form of the drug cisplatin. Most famously, the cyclist Lance Armstrong was treated with cisplatin for testicular cancer.
Now the researchers, based in the Department of Chemistry, at the University of Warwick, are working closely with Warwick Ventures, the university’s technology transfer office, to seek partners to help develop the potential of osmium through more extensive biological tests. The team will be presenting their work on 9 December at the national university technology showcase event, Bioversity.
Professor Peter Sadler, of the Department of Chemistry, explained: “Although cisplatin has been proven to be a very successful treatment; it is not useful for all kinds of cancer. It is also quite a toxic therapy, which can produce side effects and, from a clinical point of view, cells can also become resistant to platinum.”
Osmium, with its special chemical properties, offers a new potential solution to an unmet clinical need. It has shown huge promise in treating several different types of cancer cell, including ovarian and colon cancers which have been developed and tested in the laboratory. The metal also has another advantage in that it is a much cheaper alternative to platinum.
Professor Sadler, along with post-graduate researcher Sabine van Rijt, is working to develop new compounds using Osmium, which they hope will lead to the development of drugs which could be used in combination therapies alongside existing drugs such as cisplatin.
“The compounds we have been developing are very promising,” says Sabine van Rijt. “We’re building a picture of how different compounds might interact with DNA in cancer cells. By making changes to the coating, or ligand, on the metal, we can also affect not just how it interacts, but the rate of interaction. During this design process we can also make changes which can control the activity of the compound.”
She added: “Another advantage is that these compounds are not cross-resistant with platinum. They kill the cancerous cells in a different way, so they could be used alongside platinum in combination therapies.”
The team’s research is being presented on 9 December at Bioversity 2008, a national university technology showcase event. Bioversity is part of the biotechnology conference, Genesis 2008, organised by The London Biotechnology Network.
Must providers scare patients into cancer screening? By Greg Freiherr
“If you are a woman over 35, be sure to schedule a mammogram. Unless you’re still not convinced of its importance. In which case, you may need more than your breasts examined.” —From an old American Cancer Society Poster For every 1000 women aged 40 to 74 years who participated in screening, 3.9 diagnosed with breast cancer died compared with 5.0 among those who did not participate. The absolute benefit in terms of reduced deaths due to mammography screening, therefore, is about one in 1000. This may not come as a surprise to women's health experts. Patients are another story. In a survey of more than 10,000 people in nine European countries, researchers at the Max Planck Institute for Human Development in Berlin found that 92% of women reported they either did not know how much mammography reduces mortality or they vastly overestimated the benefit, believing the benefit to be one in a hundred rather than one in a thousand. Many thought the benefit was even greater. The results, published online Aug. 12 in the Journal of the National Cancer Institute, showed that more than 40% of women surveyed in France, the Netherlands, and the U.K. believed the reduction in mortality was one in 10 or even one in 5. This kind of faith in cancer screening is not restricted to women and mammography. The researchers found that 89% of men quizzed about the benefits of screening for prostate-specific antigen overestimated the benefit by as much as women did for mammography. The problem stems from the widespread campaigns, particularly in Western nations, aimed at increasing participation in screening programs. These campaigns try to persuade not through reasonable arguments but with emotional ones. When considering that mammography uses ionizing radiation and that multiple exposures over extended periods of time carry long-term risks of cancer, the inability of patients to properly assess the benefits of this exposure raises questions about whether they can provide informed consent. Adding to the downside for both mammography and PSA screening is the harm that may come from false positives that lead to unnecessary invasive follow-up procedures, such as biopsy and treatment. In an editorial accompanying the research results, Drs. Lisa M. Schwartz and Steven Woloshin of the Dartmouth Institute for Health Policy and Clinical Practice in Hanover, NH, suggested that messages promoting the use of screening should be based on facts. In the context of results citing the lower than widely believed benefits from prostate and breast cancer screening, they noted that prostate screening leads to overdiagnosis of between 10 and 30 patients for every 1000 screened and to unnecessary biopsy from false-positive mammograms in 50 to 200 of every 1000 women screened. Schwartz, a Dartmouth associate professor of medicine and community and family medicine, told Oncology News International that screening advocates should describe the benefits as well as the risks associated with overdiagnosis and overtreatment. "I think they should say something like: ‘Mammograms (PSA tests) have been shown to lower the chance of dying from breast cancer (prostate cancer). But (these tests) also have harms. We'll give you the information about the benefits and the harms so you can make a decision that is right for you.'" Doing so would mark a quantum shift in screening advocacy. Decades of ad campaigns designed to increase the number of women participating in routine mammography, for example, have created the perception of mammography as a powerful tool for reducing deaths from breast cancer. In their JNCI editorial, Schwartz and Woloshin state that "selling screening can be easy. Induce fear by exaggerating risk. Offer hope by exaggerating the benefit of screening. And don't mention harms." But is this how healthcare should be practiced? Not according to Schwartz and Woloshin: "We need to move from selling screening to helping people realize that screening is a genuine choice. That means routinely giving people the information needed to make these choices."
Enhancing The Effects Of Platinum-based Anti-cancer Drugs
ScienceDaily (June 2, 2009) — Researchers have now identified a way to enhance the in vitro anticancer effects of the commonly used platinum-based drug cisplatin and hope that it might be possible to translate these data into the development of a clinical strategy to enhance the anti-cancer effects of platinum-based drugs.
Daqing Li and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified in vitro and in mice a way to enhance the anticancer effects of the commonly used platinum-based drug cisplatin.
For many forms of cancer, including testicular, ovarian, and lung cancer, platinum-based drugs that cause DNA damage are the first choice treatment. However, the utility of these drugs is often limited by the enhanced ability of cancer cells to repair their DNA. As the MRN protein complex, which contains the protein RAD50, has a key role in the molecular pathways that control DNA repair in human cells, Li and colleagues set out to test the hypothesis that attenuating the function of the MRN protein complex might sensitize cancer cells to the effects of cisplatin.
The hypothesis was proven using a genetic approach to disrupt MRN function. Specifically, human squamous cell carcinoma cells resistant to the toxic effects of cisplatin became sensitive to the drug when it was combined with an adenoviral vector that drove expression of a dominant-negative RAD50 protein in the cancer cells. Importantly, the combination therapy had potent anti–cancer cell effects in vitro and in mice transplanted with human squamous cell carcinoma cells resistant to cisplatin. The authors therefore hope that it might be possible to develop a clinical strategy to attenuate MRN function and enhance the anticancer effects of platinum-based drugs.
Daqing Li and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified in vitro and in mice a way to enhance the anticancer effects of the commonly used platinum-based drug cisplatin.
For many forms of cancer, including testicular, ovarian, and lung cancer, platinum-based drugs that cause DNA damage are the first choice treatment. However, the utility of these drugs is often limited by the enhanced ability of cancer cells to repair their DNA. As the MRN protein complex, which contains the protein RAD50, has a key role in the molecular pathways that control DNA repair in human cells, Li and colleagues set out to test the hypothesis that attenuating the function of the MRN protein complex might sensitize cancer cells to the effects of cisplatin.
The hypothesis was proven using a genetic approach to disrupt MRN function. Specifically, human squamous cell carcinoma cells resistant to the toxic effects of cisplatin became sensitive to the drug when it was combined with an adenoviral vector that drove expression of a dominant-negative RAD50 protein in the cancer cells. Importantly, the combination therapy had potent anti–cancer cell effects in vitro and in mice transplanted with human squamous cell carcinoma cells resistant to cisplatin. The authors therefore hope that it might be possible to develop a clinical strategy to attenuate MRN function and enhance the anticancer effects of platinum-based drugs.
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