Miracle Man of Miracle Drugs
Dr. Yellapragada Subbarow

Anti-folic Acid
Anti-folics against Leukaemia come from Folics against Anaemia

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 the steroids.

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.