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

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign www.bjcancer.com

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Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.

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

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

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

Summary Guanazole (3,5-diamino-1,2,4-triazole; NSC 1895) was found to inhibit the incorporation of adenine, hypoxanthine, and uridine into DNA to a much greater extent than into RNA in L1210 leukemia cells in vivo . Thymidine incorporation into DNA was inhibited with concomitant accumulation of dTTP in L1210 cells. Leucine incorporation into protein was not inhibited. The incorporation of formate- 14 C into purine nucleotides was partially inhibited by guanazole and was accompanied by decreased labeling of nucleic acids; the effect on DNA synthesis was more pronounced than that on RNA. Similar results were obtained in human epidermoid carcinoma cells in culture. Guanazole inhibited the reduction of ribonucleotides to deoxyribonucleotides catalyzed by enzyme preparations from human epidermoid carcinoma cells. The effects of guanazole on DNA synthesis and on ribonucleotide reductase were similar to those of hydroxyurea. The experimental evaluation of guanazole against L1210 leukemia showed that dosage scheduling and route of implantation of L1210 cells were determining factors in the efficacy of the drug. When guanazole was given i.p. every 3 hr for 8 doses for a least 3 courses of treatment (Days 1, 5, and 9) after i.p. implantation of 10 5 L1210 cells, significant numbers of mice survived. In this respect also, the compound was similar to hydroxyurea.

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Inhibition of Ribonucleotide Reductase, DNA Synthesis, and L1210 Leukemia by Guanazole

The two-drug combination of cyclophosphamide plus adriamycin was found to be therapeutically potentiating against four different C3H mammary tumor lines, the B16 melanoma, the Ridgway osteogenic sarcoma, and the P388 leukemia. The potentiation was not schedule dependent.

Cyclophosphamide-adriamycin combination chemotherapy of transplantable murine tumors.

Experimental evaluation of potenital anticancer agents. XVII. Kinetics of growth and regression after treatment of certain solid tumors.

Summary Following the observation of Huggins et al. , preliminary experiments have been carried out with the view to developing parameters necessary in the adaption of the 7,12-dimethylbenzanthracene (DMBA)-induced mammary adenocarcinoma in the female rat for the routine evaluation of potential anticancer agents being considered for trial against certain cancers of the breast in women or in a search for new agents possibly worthy of such consideration. The hormone dependence of the primary DMBA-induced mammary carcinoma rather closely parallels its human counterpart. This has been borne out by the response to hypophysectomy, ovariectomy, and treatment with testosterone propionate and certain other steroids. The effect of host body weight loss on tumor growth is definable to a limited extent; tumor induction utilizes a procedure (a single intragastric dose of DMBA) of relative ease and one which provides a large tumor yield; and tumor growth rates, regardless of site or size, are not too dissimilar. It would appear from the data presented by Huggins et al. and the confirmatory results presented herein that this tumor system does indeed offer a usable and promising tool for evaluating the potential of trial agents.

https://cancerres.aacrjournals.org/content/canres/26/10/2169.full.pdf

Laster Wr

Papers

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

Inhibition of Ribonucleotide Reductase, DNA Synthesis, and L1210 Leukemia by Guanazole

Cyclophosphamide-adriamycin combination chemotherapy of transplantable murine tumors.

Experimental evaluation of potenital anticancer agents. XVII. Kinetics of growth and regression after treatment of certain solid tumors.

Induced Mammary Carcinoma in the Female Rat as a Drug Evaluation System