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.

A controlled, prospective, randomized study evaluated the use of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or radiotherapy in the treatment of patients who were operated on and had histological confirmation of anaplastic glioma. A total of 303 patients were randomized into this study, of whom 222 (73%) were within the Valid Study Group (VSG), having met the protocol criteria of neuropathology, corticosteroid control, and therapeutic approach. Patients were divided into four random groups, and received BCNU (80 mg/sq m/day on 3 successive days every 6 to 8 weeks), and/or radiotherapy (5000 to 6000 rads to the whole brain through bilateral opposing ports), or best conventional care but no chemotherapy or radiotherapy. Analysis was performed on all patients who received any amount of therapy (VSG) and on the Adequately Treated Group (ATG), who had received 5000 or more rads radiotherapy, two or more courses of chemotherapy, and had a minimum survival of 8 or more weeks (the interval that would have been required to have received either the radiotherapy or chemotherapy). Median survival of patients in the VSG was, best conventional care: 14 weeks (ATG: 17.0 weeks); BCNU: 18.5 weeks (ATG: 25.0 weeks); radiotherapy: 35 weeks (ATG: 37.5 weeks); and BCNU plus radiotherapy: 34.5 weeks (ATG: 40.5 weeks). All therapeutic modalities showed some statistical superiority compared to best conventional care. There was no significant difference between the four groups in relation to age distribution, sex, location of tumor, diagnosis, tumor characteristics, signs or symptoms, or the amount of corticosteroid used. An analysis of prognostic factors indicates that the initial performance status (Karnofsky rating), age, the use of only a surgical biopsy, parietal location, the presence of seizures, or the involvement of cranial nerves II, III, IV, and VI are all of significance. Toxicity included acceptable, reversible thrombocytopenia and leukopenia.

Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A cooperative clinical trial

To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

https://cancerres.aacrjournals.org/content/canres/60/7/1878.full.pdf

Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental Drug-resistant 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

Publisher Summary This chapter provides an overview of some of the relevant chemistry (general chemistry, preparation methods, and analytical methods) of the nitroso carcinogenic compounds and discusses the pathological lesions induced by these compounds and their mutagenic activity. Experimental studies on compounds like dimethylnitrosamine showed that they cause liver necrosis in rats, accompanied by hemorrhages into the liver and lungs and frequently an associated hemorrhagic ascites and blood in the lumen of the gut. Acute toxicity of other dialkyl and related nitrosamines cause liver damage, hemorrhagic lung lesions, convulsions, and coma. The neoplastic changes in the body organs (live, kidney, bladder, nose and nasal sinuses, lungs and bronchi, alimentary canal, nervous system, and skin) and the development of the malignant lesion caused by carcinogenic nitroso compounds are also illustrated in the chapter with the help of animal models. The variation in the response of different organs to the carcinogenic nitroso compounds is of interest in relation to the biochemical changes that may be essential for the initiation of a carcinogenic change. Many carcinogenic nitroso compounds are mutagenic. The nitroso mutagens act by the alkylation of the genetic material. The chapter also discusses the metabolism of nitroso carcinogens both in vivo and in vitro, along with their biochemical effects. The induction of cancers by single doses of rapidly eliminated nitroso carcinogens implies an interaction between the carcinogen and/or a product of its decomposition with some component or components of the cells, which must occur within a short time after administration. The nature of the proximate carcinogen and some of its possible interactions with cellular components and some serious carcinogenic hazards caused by the nitroso compounds are also discussed in the chapter.

Carcinogenic Nitroso Compounds

Summary In quantitative therapeutic studies 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962) and 1-(2-chloroethyl)-1-nitrosourea (NSC-47547) have been shown to have marked activity against intraperitoneal (I.P.) L1210 leukemia when administered by the I.P., subcutaneous, or oral route. This class of compounds is the first to be observed to possess an encouraging degree of activity against intracerebrally inoculated L1210 leukemia. Of the “active” derivatives of 1-methyl-1-nitrosourea studied to date, only those which have a higher degree of lipoid solubility and are essentially not ionized have shown capacity to affect intracerebral (I.C.) L1210 leukemia. Evidence has been obtained which suggests that the mechanism of action (at the biochemical level) of 1-methyl-1-nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea may be similar to that of certain well known alkylating agents. Experiments with bilateral implants of an alkylating agent-sensitive and -resistant plasmacytoma in hamsters showed the latter tumor to be cross-resistant to these compounds.

https://cancerres.aacrjournals.org/content/canres/23/5/725.full.pdf

McCALEB Gs

Papers

Experimental evaluation of potential anticancer agents VIII. Effects of certain nitrosoureas on intracerebral L1210 leukemia.