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

Mechlorethamine.- Cyclophosphamide.- Chlorambucil.- Melphalan.- Busulfan.- Methotrexate.- 6-Mercaptopurine.- 5-Fluorouracil.- Cytosine Arabinoside.- Hydroxyurea.- Actinomycin D.- Mithramycin.- Vinblastine.- Vincristine.- Procarbazine.- Prednisone and Prednisolone.- Investigational Agents.- 1,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU).- Daunorubicin (Daunomycin, rubidomycin).- Dimethyl triazeno imidazole carboxamide.- Streptozotocin.- Dibromomannitol.- Methyl-GAG.- Mitomycin C.- Streptonigrin.- L-asparaginase.

Single Agents in Cancer Chemotherapy

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is known to be detoxified by a denitrosation reaction catalyzed by glutathione-dependent enzymes in rat liver cytosol (R. E. Talcott and V. A. Levin, Drug Metab. Dispos., 11:175-176, 1983). Using a modification of their procedure, we have measured the ability of different purified rat glutathione transferase isoenzymes to denitrosate BCNU. The catalytic efficiencies of the isoenzymes for the denitrosation reaction expressed as the ratio of Vmax to Km were as follows (isoenzyme, Vmax/Km): 1-2, 2.3; 3-3, 12.2; 3-4, 29.2; and 4-4, 26.1. Thus, the class mu isoenzymes containing subunit 4 are by far the best catalysts of the BCNU denitrosation reaction. The class pi transferase 7-7 and class alpha transferases 1-1 and 1-2 demonstrated very weak catalytic activity with BCNU. Determination of the glutathione transferase isoenzyme profiles of 9L rat brain tumor cells and the BCNU-resistant 9L-2 subline by immunoblotting revealed that although the resistant 9L-2 cells contain lower total glutathione transferase activity than 9L cells, they have elevated levels of the class mu transferases. Also, the class pi transferases were found to be down-regulated in 9L-2 as compared with 9L cells. Thus, the increased resistance of 9L-2 cells to BCNU may, in part, be explained by up-regulation of class mu transferase expression with consequent increased capacity for BCNU detoxication. Further support for this hypothesis comes from the fact that pretreatment of 9L-2 cells with the glutathione transferase inhibitors ethacrynic acid or triphenyltin chloride enhanced the cytotoxic effects of BCNU. These results suggest that the class mu transferases play a role in the resistance of brain tumor cells to BCNU.

Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells.

✓ The authors review treatment and results in 45 cases of medulloblastoma arising in childhood. The surgical mortality rate observed was 11%. Of those completing postoperative cerebrospinal irradiation at this institution, 53% have survived for 3 years, 41% for 5 years, and 22% for 10 years. The extent of surgical resection of the cerebellar tumor had no significant bearing on the prognosis. Those cases remaining free of recurrent disease had received significantly higher doses of postoperative irradiation, approaching 5000 rads to the whole brain or posterior fossa and 4000 rads to the spinal axis. Repeat irradiation and chemotherapy (vincristine, the nitrosoureas, and methotrexate) provided good palliation in most cases and significantly extended the survival time. However, 28 of 29 patients who developed locally recurrent or metastatic disease have died. Vincristine was considered the chemotherapeutic drug of choice and in 14 cases its use was associated with remissions lasting 2 to 18 months. The comb...

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Papers

BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea; NSC-409962) in the treatment of malignant brain tumor--a preliminary report.