The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs. Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers.

Timeline: Chemotherapy and the war on cancer.

The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II-related programs, and the effects of drugs that evolved from them, that provided the impetus to establish in 1955 the national drug development effort known as the Cancer Chemotherapy National Service Center. The ability of combination chemotherapy to cure acute childhood leukemia and advanced Hodgkin's disease in the 1960s and early 1970s overcame the prevailing pessimism about the ability of drugs to cure advanced cancers, facilitated the study of adjuvant chemotherapy, and helped foster the national cancer program. Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments.

https://cancerres.aacrjournals.org/content/canres/68/21/8643.full.pdf

A History of Cancer Chemotherapy

Exceptional advances in molecular biology and genetic research have expedited cancer drug development tremendously. The declared paradigm is the development of 'personalized and tailored drugs' that precisely target the specific molecular defects of a cancer patient. It is therefore appropriate to revisit the intellectual foundations of the development of such agents, as many have shown great clinical success. One hundred years ago, Paul Ehrlich, the founder of chemotherapy, received the Nobel Prize for Physiology or Medicine. His postulate of creating 'magic bullets' for use in the fight against human diseases inspired generations of scientists to devise powerful molecular cancer therapeutics.

Paul Ehrlich's magic bullet concept: 100 years of progress.

Biological and Phytochemical Screening of Plants

The indole nucleus is an important element of many natural and synthetic molecules with significant biological activity. This review covers some of the relevant and recent achievements in the biological, chemical and pharmacological activity of important indole derivatives in the areas of drug discovery and analysis.

Biomedical Importance of Indoles

Summary A phytochemical investigation of the plant Vinca rosea Linn. has demonstrated that a number of alkaloidal substances can be obtained with antitumor activity. Over 30 alkaloids have been obtained, of which four—vinblastine, vinleurosine, vincristine, and vinrosidine—are known definitely to be active. Chemically these compounds are closely related to one another and to two monomeric alkaloids, vindoline and catharanthine. The structure of these latter two compounds has been determined, and partial structures for the biologically active alkaloids have been proposed. They represent a new class of large complex dimeric alkaloids containing both indole and dihydroindole moieties. Experimentally, a strain-specific, transplantable, acute, lymphocytic leukemia (P-1534) carried in DBA/2 mice served as a bioassay for obtaining these compounds and for predicting their clinical activity. Vinblastine, vincristine, and vinrosidine are capable of prolonging and/or “curing” mice of the P-1534 leukemia even when therapy is delayed until a near-terminal state of generalized disease. Resistance to an additional challenge of leukemic cells has been observed in these “cured” animals. Parenteral administration of vincristine has been demonstrated to “cure” mice given intracranial implants of the P-1534. The experimental tumor spectrum and toxicological studies are presented and discussed. Biochemical studies performed to date do not reveal any effect on cellular respiration, glycolysis, protein or nucleic acid synthesis. The mechanisms of action of these compounds, which may differ within the group as well as from those of other known agents, remain to be determined. Only two of these compounds, vinblastine and vincristine, have received extensive clinical evaluation. In spite of their close similarity, chemically, a somewhat different group of human neoplasms responds to these compounds, and there has been a singular lack of cross-resistance between these two drugs and any other oncolytic drug now in wide use. Vinblastine has proved effective in chorioepithelioma, Hodgkin9s disease, and other lymphomas, and a number of beneficial results have been obtained in carcinoma of the breast and bronchus. In addition, there have been smaller numbers of a variety of other neoplasias reported as responding to this compound. Vincristine has been striking in its ability to induce complete hematological remission of the acute leukemias of childhood, both lymphocytic and myelogenous in type. Responses have also been reported in a number of other malignancies. The problems and obstacles encountered in obtaining a full realization of the clinical efficacy of these new types of oncolytic compounds are discussed in addition to areas of clinical application other than those previously reported.

https://cancerres.aacrjournals.org/content/canres/23/8_Part_1/1390.full.pdf

Burnett Jp

Papers

The Vinca Alkaloids: A New Class of Oncolytic Agents