A revolutionary new way of delivering chemotherapy, 1,000 times stronger than normal, offers hope to women battling ovarian cancer.
The anti-cancer drugs are put directly into the abdomen, via a catheter, instead of being injected into the bloodstream using an intravenous drip.
A trial of the new technique, known as intraperitoneal chemotherapy, has just been launched across the UK from Barts and The London School of Medicine.
The new chemotherapy treatment put directly into the abdomen is 1,000 times stronger than normal and gives hope to ovarian cancer sufferers.
Ovarian cancer is one of the deadliest forms of the disease. Every year, 6,600 women are diagnosed and 4,300 will die from it. But Dr Chris Gallagher, who heads the study in the UK, is confident this advance will show an increase in survival of around 20 per cent.
He said: ‘Ovarian cancer tends to spread, or recur, within the abdominal cavity. It is unusual for it to spread to other parts of the body – in that way, it’s different from many other cancers.
‘By giving the treatment directly into the area where the cancer is located, we have the potential to expose the tumour to much higher concentrations of the drug.
‘We need to increase the efficacy of chemotherapy drugs against ovarian cancer, so we won’t be able to reduce the dose. But increasing their intensity will get a better response.’
Hitting the tumour harder could also reduce its ability to become resistant to chemotherapy drugs, a common problem with ovarian cancer. Because more cancer cells are destroyed in each dose of chemotherapy, there are fewer left with the opportunity to evolve and develop ways of surviving the treatment.
The PETROC study, a joint UKCanadian trial, will recruit 150 women newly diagnosed with advanced ovarian cancer. It will compare the effect of identical doses of two conventional chemotherapy drugs – paclitaxel plus either carboplatin or cisplatin, which are both forms of platinum – when given directly into the abdomen or intravenously.
Platinum is widely used in the treatment of cancer, often in combination with other drugs. It works by binding to tumour cell genes.
Dr Gallagher said: ‘Earlier studies indicate that when given directly the platinum-based drug is about 10 times more concentrated and the paclitaxel is about 1,000 times higher than when given intravenously.
‘As both drugs are then absorbed into the bloodstream, the sideeffects such as nausea, tiredness and hair loss are similar.’
During the treatment, a small catheter is inserted into the abdomen during surgery or under local anaesthetic.
Each course of chemotherapy takes around six hours – slightly longer than conventional treatment.
Afterwards, most women experience temporary abdominal swelling.
Dr Gallagher hopes this new trial will identify the patients most likely to benefit and resolve any worries about catheters causing pain. In previous studies around 5 per cent found the method too painful.
Ovarian cancer has been called the ‘silent killer’, as it is often so advanced by the time it is diagnosed that two out of three women will not survive. Just 4 per cent of women are confident they could spot the signs of the disease, according to a poll carried out last week.
Symptoms, which include pelvic and abdominal pain, bloating and difficulty eating, can be confused with Irritable Bowel Syndrome.
Professor Iain McNeish, a specialist at Barts and The London Hospital, often sees patients who were initially told they had a gastric rather than gynaecological problem.
He does not blame doctors, as most GPs will only ever see three or four cases of ovarian cancer.
But he said: ‘For IBS to appear for the first time in a woman in her 50s, or older, is very rare. If a woman regularly gets these symptoms, she should see her GP and ask them to rule out ovarian cancer.’
In most cases, it won’t be a tumour, but if it is ovarian cancer, early diagnosis is the key, says Professor McNeish.
‘The single strongest predictor of survival is how advanced your cancer is at the time of diagnosis.
‘We hope that intraperitoneal chemotherapy will give women with advanced ovarian cancer a better chance of beating the disease in the long term.’
Jane Symons – 2nd March 2010
Platinum(II)-Acyclovir Complexes: Synthesis, Antiviral and Antitumour Activity
M. Coluccia, A. Boccarelli, C. Cermelli, M. Portolani, and G. Natile
Metal-Based DrugsVolume 2 (1995), Issue 5, Pages 249-256doi:10.1155/MBD.1995.249
Dipartimento di Scienze Biomediche e Oncologia Umana, Piazza G. Cesare11, Bari 1-70124, Italy2Dipartimento di Scienze Biomediche, Università di Modena, Modena, Italy3Dipartimento Farmaco-Chimico, Università di Bari, Bari, Italy
Received 29 June 1995; Accepted 27 July 1997
Copyright © 1995 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A platinum(II) complex with the antiviral drug acyclovir was synthesized and its antiviral and anticancer properties were investigated in comparison to those of acyclovir and cisplatin. The platinum-acyclovir complex maintained the antiviral activity of the parent drug acyclovir, though showing a minor efficacy on a molar basis (ID50 = 7.85 and 1.02 μΜ for platinum-acyclovir and cisplatin, respectively). As anticancer agent, the platinum-acyclovir complex was markedly less potent than cisplatin on a mole-equivalent basis, but it was as effective as cisplatin when equitoxic dosages were administered in vivo to P388 leukaemia-bearing mice (%T/C = 209 and 211 for platinum-acyclovir and cisplatin, respectively). The platinum-acyclovir complex was also active against a cisplatin-resistant subline of the P388 leukaemia (%T/C = 140), thus suggesting a different mechanism of action. The DNA interaction properties (sequence specificity and interstrand cross-linking ability) of platinum-acyclovir were also investigated in comparison to those of cisplatin and [Pt(dien)Cl]+, an antitumour-inactive platinum-triamine compound. The results of this study point to a potential new drug endowed, at the same time, with antiviral and anticancer activity and characterized by DNA interaction properties different from those of cisplatin.
The local three-dimensional structure of DNA is important in interactions with proteins involved in repair, transcription, recombination, and chromatin condensation. Recently, it has been proposed that antibiotics can induce formation of DNA structures that can recruit these proteins with cytotoxic results. The best-studied example of this phenomenon is the antitumor medicine cisplation, a tetra coordinate platinum complex [cis-Pt (NH2) 2Cl2]. Cisplatin is used alone or in combination with other antitumor agents to treat a variety of tumors including testicular, ovarian, bone, and lung cancers. This platinum complex forms inter- and intrastrand cross-links in double-stranded DNA with the latter adduct comprising 90% of DNA lesions. These bonds arise from displacement of chloride ligands on platinum by N-7 atoms of two neighboring guanines. Structural studies on intrastrand cross-linked DNA adducts show that the double helix is strongly bent toward the major groove.
Bent structure of the DNA-cisplatin adduct are specifically recognized by several DNA-binding proteins that include nucleotide excision repair (NER) proteins and high-mobility-group proteins such as HMG-1. It has been proposed that the cytotoxicity of cisplatin adducts is a complicated process mediated by specific interactions with these proteins. Cellular process such as transcription and apoptosis (programmed cell death) are affected by formation of cisplatin-DNA adducts. The lesions themselves and the adduct-protein complexes are likely to interfere with transcription. NER proteins are recruited to repair the lesion, but excision repair is prone to introduction of DNA strand breaks.
Accumulation of these breaks will ultimately induce apoptosis as the DNA becomes too damaged to function. Similar mechanisms have also been proposed to account for cytotoxicity of other DNA-binding medicine such as ditercalinium. This bifunctional molecule forms noncovalent adducts with DNA that are also highly bent. Cytotoxicity is thought to arise from induction of abortive repair pathways that lead to DNA strand breaks.
Interactions of the cisplatin-DNA adduct with HMG proteins may also contribute to its cytotoxicity. Binding of HMG proteins may incorrectly signal that the damaged region of DNA is transcriptionally active and prevent condensation into folded chromatin structures. These complexes might also perpetuate the lesion by shielding the DNA-cisplatin adducts from repair.