KEY POINTS:
Little by little, the enigma of childhood leukaemia is beginning to unravel. Its causes remain a mystery but Dr Ian Morison from Otago University's Cancer Genetics Laboratory knows that acute lymphoblastic leukaemia - the most common of childhood cancers - is present even before birth.
"It's very clear
that the kids who have it, by the time they get to birth, already have a substantial number of leukaemic cells in their blood," he said.
Dr Morison's research is trying to pinpoint the exact period between conception and birth when leukaemic cells start to develop, and to better understand what genetic factors make that happen.
The team have already identified some markers they believe to be involved.
Eventually, their research could lead to tests showing whether a child is susceptible to leukaemia - but Dr Morison cautioned that this was still a distant possibility.
Leukaemia is often seen as a children's cancer, which is only partly true. It makes up a third of all childhood cancers in New Zealand but about 10 times more adults than children are affected.
The survival rate is much higher than it used to be, although more than 30 per cent of New Zealanders who get leukaemia still die.
And the causes of childhood leukaemia remain elusive.
"There's been a huge amount of interest in lots and lots of different things like Vitamin K and electromagnetic fields," Dr Morison said. "The consensus is against the involvement of factors like that.
"Nobody knows what causes it.
"As countries have modernised over the last several decades, the rate has clearly gone up.
"There seems to be something about modern life, but that doesn't mean it's cellphone towers - it could equally be the nutrition of the mum. It could be any one of a thousand factors we hadn't thought of."
Epigenetics is a promising new area of interest.
Traditionally, cancers were thought to be caused by gene mutations.
"A mutation can affect just a single letter of DNA and disrupt a very important gene that puts brakes on a cell, controlling the cell's growth," said Dr Morison. "It's like if a cable breaks on the handbrake of a car."
Otago's Cancer Genetics Laboratory is looking at epigenetic changes, which modify cell function without mutation taking place.
The process, called methylation, modifies parts of the DNA, typically silencing the genes that control cell function. The result is the same as a mutation.
"It turns that gene off, and if that gene is critically important to control normal cell division, the cell gets out of control and it just grows and grows."
Methylation occurs normally in genes, but abnormally in cancer.
"As far as we know, cancer's unusual in that it uses this mechanism wrongly, and it switches off genes that would otherwise not be switched off. Methylation occurs in normal tissue growth and organ development, but not to the scale that we see in cancer."
Drugs that reverse the process, dubbed demethylating agents, have shown some success in clinical trials overseas in adults with leukaemia, although Dr Morison warned that these drugs were not yet sophisticated enough to target only the affected genes.
But newly developed drugs are having a profound impact on leukaemia. The most spectacular success story has been Glivec, now the main treatment for chronic myeloid leukaemia (CML). One of the earliest examples of targeted drugs, Glivec blocks the cellular signals that spur cancer growth.
Much like breast cancer drug Herceptin, its arrival in 2002 was much vaunted, but its price - and the small number of patients it would help - meant Pharmac was initially reluctant to fund it. However, after an emotional campaign the Government drug agency agreed to subsidise the drug.
Leukaemia and Blood Foundation medical director Dr Peter Browett said before Glivec, people with the disease survived an average of 4 1/2 years.
Latest results have found 90 per cent of CML patients on Glivec still alive after five years, with many in complete remission.
"Glivec is one of those medical discoveries that you only see once or twice in a medical career. It's the model for the whole direction of cancer research at the moment," said Dr Browett, a haematologist and researcher at Auckland Hospital and the Auckland Medical School.
Cost was an issue with all new drugs, he said, and pricing here often depended on the drug's price in North America.
"Drug development is very time-consuming. It needs to be done carefully, and it's expensive. It's not unique to any drug.
"Having said that, there are some smart drugs that are fortuitously less expensive."
One of the better-known examples of this is ATRA (all-trans-retinoic-acid).
Discovered by Chinese scientists, the relatively cheap drug is now the treatment of choice for acute promyelocytic leukaemia.
Dr Browett said research now focused on designing compounds that would inhibit a cancer's growth. In leukaemia treatment, FLT3 inhibitors - which block a vital protein in cancer growth - are looking promising in clinical trials overseas.
Several New Zealand patients are also involved in clinical trials for Mylotarg, which works on the same principle as Herceptin. It binds to a protein on the surface of myeloid leukaemia cells in more than 80 per cent of patients and then releases a toxin into the cell, killing it.
Enzyme inhibitor Fodosine, a compound developed by Government-owned Industrial Research, also looks promising.
Licensed to US company BioCryst Pharmaceuticals, the drug is in clinical trials for T-cell leukaemia, B-cell acute lymphoblastic leukaemia, and chronic lymphocytic leukaemia.
Dr Browett said researchers were now trying to uncover the genetic factors that caused some patients to go into remission, while others with the same condition did not, even when given the same therapy.
Modern chemotherapy was now yielding better results, while bone marrow and stem-cell transplants also had better success rates.
"We're now transplanting more patients, we're transplanting older patients and we're transplanting patients who don't have sibling donors.
"There's been quite significant advances in the last decade and those are continuing to develop."
Line between life and death
Rotorua grandmother Carol Clarke owes her life to Glivec, and says it's a good thing the drug is now publicly funded.
She was diagnosed with chronic myeloid leukaemia in April 2000, and was deemed a good candidate for a clinical trial of what was then an experimental drug.
As in most cases, her leukaemia was picked up accidentally.
"I was feeling extremely tired, and very hot and sweaty, with flu-like symptoms. I thought it was menopause, but it was bigger than menopause."
She started taking Glivec capsules six months later as part of an international clinical trial. She was the first New Zealand patient to join the trial.
Her cancer has been in remission since April 2001, but she continues to take four capsules daily.
"Four hundred milligrams a day. It's not a lot, is it, between life and death?"
