SubbaRow got Aminopterin, which reverses the action
of folic acid, synthesised when reports of a clinical collaborator
indicated that chemicals resembling the vitamin arrest the growth
of cancer cells. He thus initiated the chemotherapeutic approach
to the treatment of cancer. Methotrexate, a derivative of Aminopterin,
has since then been the drug of choice in childhood leukaemia and
many adult cancers.
SubbaRow and his team of organic and biological chemists had isolated
folic acid from liver and a microbial source and then synthesized
it in 1945. Folic acid quite fortuitously led to an entirely new
line of fighting cancer with chemical agents, thanks to SubbaRow’s
ever probing, forever analytical mind.
SubbaRow had a report from an investigator that folic acid obtained
from fermentation broths had to be digested with hydrochloric acid
to make it as active as folic acid from liver in promoting the growth
of a certain microbe. The two folic acids were indeed different.
An analysis showed that fermentation folic acid has three molecules
of glutamic acid whereas liver folic acid has only one glutamic
molecule. In mice, fermentation folic acid stopped and even eliminated
cancer cells and liver folic acid, on the other hand, promoted the
growth of cancer cells. Cancer workers began to clamour for fermentation
folic acid and Jim Boothe synthesised it early in 1947.
SubbaRow supplied this three-glutamic folic acid or teropterin
to Dr Richard Lewisohn of New York's Mount Sinai Hospital and established
a full evaluation programme with his old friend Sidney Farber at
Boston’s Children Hospital. In cooperation with other Boston
hospitals, Farber administered teropterin to cancer patients for
whom no known treatment offered any hope of cure.
Improvement observed in many of the first group of Boston’s
90 patients was neither constant nor lasting but it occurred frequently
enough to encourage further study. Particularly remarkable was the
great sense of well-being the patients felt. They appeared to be
more energetic, ate better, showed less irritability and fear of
death, suffered less from pain, and needed less of drugs to alleviate
pain or sleep.
And Lewisohn reported the remarkable prolongation of life and considerable
easing of pain of Babe Ruth. The celebrated baseball player had
entered hospital with his cancer spread despite surgery and radiation
treatment. He was in terrific pain, could not sleep, could not eat
solid food and could hardly talk. With daily injections of teropterin,
the tumour in his neck shrivelled in less than six weeks. Ruth had
hardly any pain. He could eat solid food, sleep, talk better and
gained 12 pounds. Although he was not cured, Ruth's case roused
considerable interest in professional circles.
A thorough investigation of teropterin following insistent demand
for it from clinics throughout the world showed it was at best a
palliative. The temporary shrivelling of tumours reported by Lewisohn
and Farber has never been satisfactorily explained. Teropterin was
withdrawn as a cancer drug but it served the cause of cancer fight
well by drawing attention to folic acid derivatives.
SubbaRow was set to thinking when Farber later reported that teropterin
accentuated the leukaemic process in children. Since teropterin
is a folic acid analogue, he reasoned that folic acid antagonists
- folic acid derivatives which reversed the vitamin effects of folic
acid - might inhibit leucopoiesis (white blood cell formation).
X-methyl folic acid, the first antagonist his chemists synthesised,
caused in rats a destruction of blood cells that could be stopped
with vitamin folic acid.
Folic acid antagonists were thus indicated in leukaemia to check
the increase in the number of cellular elements in the patient’s
blood especially when vitamin folic acid could keep the action of
the antagonists within bounds.
SubbaRow got his chemists to make all possible chemical compounds
closely resembling folic acid and had them tested for their vitamin
or anti-vitamin properties. And, he took two of them to Farber in
Boston. Neither saved the 21 children treated for leukaemia but
post-mortem examination of their bone marrow showed an improvement
in the formation of blood. The doctors felt justified in asking
SubbaRow for a ‘more powerful anti-folic’.
The Boston Herald on April 9, 1948 carried pictures of two boys
saved by aminopterin, the ‘powerful anti-folic synthesised
by SubbaRow’s chemists. Robert Sandler, one of the boys, was
shown with Elliot, his identical twin. It was difficult to make
out from the picture that Robert had only recently escaped from
the jaws of leukaemia whereas Elliot had never suffered a day of
sickness in all his three years. Robert and George Jason, a four-year-old
also featured in the newspaper story, were among the ten who had
responded favourably in a group of 16 leukaemic children to whom
aminopterin was administered by Farber and associates.
Doctors used to resign themselves to the death of children from
leukaemia in days or weeks, six months at best. They were now impressed
that among the Boston Ten was a child alive 20 months after leukaemia
was diagnosed and that aminopterin had effected repeated remissions
-- temporary return of the white blood cell count to its normal
range. Previously no child with leukaemia had shown two remissions.
Boston American came out the next day with the report that SubbaRow
whose chemical research had yielded the miracle drug was ‘a
Hindu’ who had previously worked at Harvard Medical School.
Although all patients, despite remissions sometimes lasting four
months, suffered relapses and any further administration of aminopterin
was futile, it was an accomplishment against a disease whose treatment
was so long associated with despair. The margin was also slim between
the effective aminopterin dose and the dose that caused blood changes
uncontrollable by vitamin folic acid.
Farber asked SubbaRow for a less toxic but more powerful anti-folic.
SubbaRow set his chemists the task of synthesising a chemical that
was as harmless as teropterin but as active as aminopterin.
METHOTREXATE, which is one-fifth as toxic as aminopterin but requires
a five-fold higher dose, is now the preferred drug. It allows physicians
to better adjust the dosage. Used in combination with other drugs,
it has prolonged the lives of children with acute leukaemia for
as long as five years. This is considered by doctors to be virtual
cures, considering how fast the children used to die previously.
Once remissions are achieved, many children feel well and enjoy
life. There is always the hope that a permanent cure will be discovered
during the extended lease on life.
Aminopterin, a brainchild of SubbaRow, has the folic molecule with
an amino radical replacing the hydroxy radical in the vitamin. It
reverses the vitamin action of folic acid and is called an anti-folic
or folic acid antagonist. It provided for the first time some semblance
of treatment for leukaemias. It initiated the chemotherapeutic approach
to treat widespread cancers or cancers not amenable to surgery.
Methotrexate, the modified aminopterin, has singly improved the
survival of young women suffering from choriocarcinoma, the cancer
of the after-birth mimicking pregnancy.
In fact, methotrexate, used initially in cancer treatment, is finding
a new place in non-cancerous diseases. It has become a fairly standard
drug in treatment of rheumatoid arthritis and psoriasis, the two
chronic disabling conditions of joints and skin.
Though needing further evaluation, methotrexate has been used successfully
in chemotherapeutic treatment of ectopic pregnancy, chronic ulcerative
diseases and asthma. It may prove to be a boon to asthmatics as
it can reduce steroid dependency and thus the complications from
Late in 1947 the conquest of cancer became the ‘magnificent
obsession’ of SubbaRow. He established at Pearl River the
first cancer research unit in any American pharmaceutical company
and supervised closely a screening programme. He wanted to set up
a new cancer research laboratory at nearby Wyckoff but died soon
after the building plans were approved. His colleagues believed
he would have conquered cancer had he lived another ten years.
Chemotherapy of cancer or treatment with drugs remains the main
hope for the eventual conquest of cancer. It owes a lot to SubbaRow
who switched to folic antagonists despite initial reports crediting
folic analogues with anticancer properties. SubbaRow relied on observation
rather than theory.
George Hitchings, a Harvard colleague of SubbaRow's, in independent
research, discovered in 1951 that purine antagonists supplement
folic antagonists in the chemotherapy of leukaemia. He lived to
receive the Nobel Prize 37 years later in 1988. SubbaRow would presumably
have shared it had Nobel permitted posthumous awards.