Cancer Chemotherapy

Excerpt

The three events that led to the development of cancer treatment began with three events in the last century: the discovery of X-rays by Wilhelm Konrad Roentgen, the use of transplantable animal-tumor models in cancer research, and the first surgical procedure developed by Halsted (radical mastectomy).

The term “chemotherapy” was coined by German chemist Paul Ehrlich who investigated the use of drugs to treat infectious diseases. He was also the first scientist to study animal models to screen a series of chemicals regarding their potential activity against diseases. Historical documents suggest the use of arsenicals started in the 1900s. Radiotherapy ad surgery were the mainstays of cancer management in the 1960s. As micrometastases and recurrence of cancer after surgery and radiation therapy became evident, combination chemotherapy started gaining significance.

Publication of the Lindskog article suggesting the success of nitrogen mustard in the treatment of lymphoma had a considerable initial effect on the development of cancer chemotherapy, including oral derivatives like chlorambucil and ultimately cyclophosphamide. The discovery of actinomycin D pioneered the search for more antitumor antibiotics, including anthracyclines, mitomycin, and bleomycin. Farber et al., in 1947, showed success in the treatment of childhood leukemia by using antimetabolites with antifolate activity, called aminopterin, later be known as methotrexate.

The successful management of choriocarcinoma and leukemias with methotrexate led to further investigations in cancer chemotherapy. And drugs like thiopurines (e.g., 6-mercaptopurine), 5-fluorouracil came into the forefront of cancer treatment.

Nowell et al. studied the association of translocation of chromosomes 9 and 22 to several leukemias, which later led to developing the first molecular targeted treatments years later (imatinib). Charles Huggins won a Nobel Prize in 1966 for investigations on hormone therapy in prostate cancer. This work was a stepping stone to a new era of hormone therapy, with the introduction of drugs like tamoxifen and anastrozole, etc.

With an increased understanding of the biology of cancer, there are now several therapeutic monoclonal antibodies available. rituximab and trastuzumab were approved during the late 1990s to treat lymphoma and breast cancer, respectively. Molecular targeted therapy is a new approach to cancer treatment. Several agents have received approval from the U.S. Food and Drug Administration (FDA) in the last decade.

Researchers are designing molecular targeted therapy on these pathways, selectively inhibiting growth, e.g., targeting cell signaling or angiogenesis, blocking protein degradation, etc. Targeted therapies are discussed as a separate topic. Immune checkpoint inhibitors PD1, PDL1, CTLA 4, which cause immune activation against cancer cells, are widely used in various cancers. Immunotherapy is discussed in a separate topic.