Chemotherapy over the Years Marwan ElBagoury 1 , Maryam Kotb 2 1 Universität Ulm - Medizinische Fakultät, Ulm, Deutschland 2 University of The People, Pasadena, CA, USA Abstract At the beginning of the 20th century, attempts to use chemotherapy for the treatment of cancer were started, and the first four decades of the 20th century were mainly dedicated to model development. There existed a dominant doubt regarding the capacity of drugs to treat advanced cancers until the success of combination of chemotherapy in treatment of acute childhood leukemia and advanced Hodgkin's disease in the 1960s and the early 1970s. Chemotherapy has undergone a lot of changes until the date, and nowadays molecular abnormalities are intensely studied to screen for potential new drugs and targeted treatments as well. The article highlights the major milestones in chemotherapy through the years. Key Words-Chemotherapy-cancer-leukemia-NCI-lymphoma-monoclonal antibodies-Rituximab- vinca alkaloids- breast cancer -targeted therapy- TKI- imatinib- Cisplatin- Carboplatin -mechlorethamine- vincristine- methotrexate- prednisone INTRODUCTION In 1910, the German chemist Paul Ehrlic started the age of chemotherapy by discovering the first antibacterial agent; a compound effective against spirochete that causes syphilis [1]. In addition, he recognized the efficacy of animal models in screening series of chemicals for their possible therapeutic effects, an achievement that had great implications on developing cancer therapy [2]. Aniline dyes were among the drugs –supposed to treat cancer- that Ehrlic was interested in, however, he was not hopeful about their success. The laboratory in which these experiments were carried out had a sign on its door that read "Give up all hope oh ye who enter" [3]. The field of cancer therapy was led by surgery and chemotherapy until 1960s. Afterwards, the new studies revealed that combination chemotherapy has the capacity to treat patients suffering many progressive cancers [4]. The combined efforts of the pediatric surgeons and the pediatric oncologists along with the radiation therapists in the 1960s and 1970s to enhance the treatment of Wilm's tumor in children represented the first fruitful application of a multifaceted tactic to treat cancer. The success of the combinations of chemotherapeutic agents in treatment of Hodgkin disease during the 1960s led to the extensive use of combination chemotherapy in treatment of nearly all types of cancers [5]. The Use of Animal Models A substantial advancement in the complexity and application of animal models in medical studies was seen during the first 4 decades of the 20th century and the years of the Great War [6]. In the early 1910s, George Clowes of Roswell Park Memorial Institute (RPMI) in Buffalo, New York, Roswell Park Memorial Institute established the first transplantable tumor systems in rodents. This was a significant advancement as it allowed the standardization of model systems, and the testing of larger numbers of chemicals as well. Afterwards, a lot of efforts were concerned with finding the ideal model system that suits cancer drug testing [7]. In 1937, the National Cancer Institute (NCI) was established through the combination of the Office of Cancer Investigations of the United States Public Health Service (USPHS), and the NIH Laboratory of Pharmacology becoming the National Cancer Institute (NCI) [8]. A manuscript by Furth et al. [9] was published in the same year unfolding the mechanism of leukemia transmission in mice from a single implanted cell that gave rise to death of the recipient. After 2 years, Charles Huggins and his team, began studying androgen levels and the occurrence of prostate cancer in dogs. Later in 1966, Huggins was awarded the Nobel Prize for medicine in gratitude of this work that showed the relationship between hormones and certain cancers [10]. World War II and the immediate Post-War Period Gases were not employed in the battleground during World War II (WWII), however, excessive research was carried out in order to study vesicant war gases [11]. In addition to the experience in WWI, the outcomes of an unintentional exposure to sulfur mustards in Italy in WWII led the way to noting that those men who were exposed to the mustard gas showed a significant depletion in bone marrow and lymph nodes as well [12]. The pharmacologists Alfred Gilman and Louis Goodman of Yale University did some research funded by the US Office of Scientific Research and Development (US OSRD) in order to study the possible therapeutic effects of Nitrogen mustard, and they found that it showed antitumor activity against murine lymphoma [13]. In 1943, the first use of a mustard compound to treat human cancer was recorded; a patient suffering from non- Hodgkin’s lymphoma, and presenting with severe airway obstruction. Gilman and Goodman succeeded in persuading Gustaf Lindskog (The thoracic surgeon who was following up the non-Hodgkin’s lymphoma patient at Yale) to give mustard to the patient. A significant, but transient regression was found in this patient and other lymphoma patients [13, 14]. Until 1946, the publication of these case reports was precluded due to the secrecy associated with the war gas program [13]. Continuous parallel advances during WWII resulted in synthesizing antifolate compounds (methotrexate); proved to achieve noticeable remissions in childhood leukemia in 1948. However, these remissions were temporary [15]. In addition to the US OSRD program studying the possible therapeutic effects of Nitrogen mustard, there was another program concerned with searching for antibiotics, and it found that Actinomycin D had antitumor activity. It was extensively used in pediatric tumors during the 1950s and 1960s [16]. In 1951, 6-thioquanine and 6- mercaptopurine were developed, and were widely used in acute leukemias [17]. In addition, they were used as immunosuppressive agents in the organ transplantation, and in the treatment of other diseases as gout, and viral infections as herpes [7]. Among the drug development programs that took place in the immediate postwar years, the largest was managed by Dr. Cornelius Rhoads at the Sloan-Kettering Institute (SKI). The murine S180 was the main model used by the SKI investigators, as it showed moderate sensitivity to identified compounds, and was smoothly transplanted with almost 100 % success [18]. At that time, many tumor systems became available, and the main concern of drug screeners was finding out which transplantable tumor was the best to predict human activity. Leukemia 1210 (L1210) model system, defined by Lloyd Law at the NCI was a murine leukemia induced by a carcinogen [19]. Skipper and colleagues at Southern Research Institute [20], and then DeVita and colleagues [21] Marwan ElBagoury et al /J. Pharm. Sci. & Res. Vol. 10(2), 2018, 316-318 316