This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Frei, E. Articles by Wang, Y. Search for Related Content PubMed PubMed Citation Articles by Frei, E., III Articles by Wang, Y.

Preclinical Studies and Clinical Correlation of the Effect of Alkylating Dose¹

Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents.

¹ This work was supported by National Cancer Institute Grant PO1-CA38497 and a grant from the Mathers Foundation.

Received 3/21/88. Revised 7/ 1/88. Accepted 8/ 9/88.

This article has been cited by other articles:

				S. Gururangan, J. Krauser, M. A. Watral, T. Driscoll, N. Larrier, D. A. Reardon, J. N. Rich, J. A. Quinn, J. J. Vredenburgh, A. Desjardins, et al. Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma Neuro-oncol, January 1, 2008; 10(5): 745 - 751. [Abstract] [Full Text] [PDF]

				K. Chen, K. Wang, A. M. Kirichian, A. F. Al Aowad, L. K. Iyer, S. J. Adelstein, and A. I. Kassis In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase-mediated cancer diagnosis and therapy Mol. Cancer Ther., December 1, 2006; 5(12): 3001 - 3013. [Abstract] [Full Text] [PDF]

				A. DeMichele, R. Aplenc, J. Botbyl, T. Colligan, L. Wray, M. Klein-Cabral, A. Foulkes, P. Gimotty, J. Glick, B. Weber, et al. Drug-Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort J. Clin. Oncol., August 20, 2005; 23(24): 5552 - 5559. [Abstract] [Full Text] [PDF]

				D. Valteau-Couanet, J. Michon, A. Boneu, C. Rodary, Y. Perel, C. Bergeron, H. Rubie, C. Coze, D. Plantaz, F. Bernard, et al. Results of Induction Chemotherapy in Children Older Than 1 Year With a Stage 4 Neuroblastoma Treated With the NB 97 French Society of Pediatric Oncology (SFOP) Protocol J. Clin. Oncol., January 20, 2005; 23(3): 532 - 540. [Abstract] [Full Text] [PDF]

				S. Gururangan, C. McLaughlin, J. Quinn, J. Rich, D. Reardon, E. C. Halperin, J. Herndon II, H. Fuchs, T. George, J. Provenzale, et al. High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Children and Adults With Newly Diagnosed Pineoblastomas J. Clin. Oncol., June 1, 2003; 21(11): 2187 - 2191. [Abstract] [Full Text] [PDF]

				W. P. Petros, G. Broadwater, D. Berry, R. B. Jones, J. J. Vredenburgh, C. J. Gilbert, J. P. Gibbs, O. M. Colvin, and W. P. Peters Association of High-dose Cyclophosphamide, Cisplatin, and Carmustine Pharmacokinetics with Survival, Toxicity, and Dosing Weight in Patients with Primary Breast Cancer Clin. Cancer Res., March 1, 2002; 8(3): 698 - 705. [Abstract] [Full Text] [PDF]

				D. Frappaz, J. Michon, C. Coze, C. Berger, E. Plouvier, C. Lasset, J. L. Bernard, J. L. Stephan, E. Bouffet, M. Buclon, et al. LMCE3 Treatment Strategy: Results in 99 Consecutively Diagnosed Stage 4 Neuroblastomas in Children Older Than 1 Year at Diagnosis J. Clin. Oncol., February 1, 2000; 18(3): 468 - 468. [Abstract] [Full Text] [PDF]

				R. J. Amato, R. Millikan, D. Daliani, L. Wood, C. Logothetis, and A. Pollack Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma Clin. Cancer Res., January 1, 2000; 6(1): 72 - 77. [Abstract] [Full Text]

				R. B. Weiss The Randomized Trials of Dose-Intensive Therapy for Breast Cancer: What Do They Mean for Patient Care and Where Do We Go From Here? Oncologist, December 1, 1999; 4(6): 450 - 458. [Abstract] [Full Text]

				A. H. Honkoop, S. A. Luykx-de Bakker, K. Hoekman, S. Meyer, O. W.M. Meyer, C. J. van Groeningen, P. J. van Diest, E. Boven, E. van der Wall, G. Giaccone, et al. Prolonged Neoadjuvant Chemotherapy with GM-CSF in Locally Advanced Breast Cancer Oncologist, April 1, 1999; 4(2): 106 - 111. [Abstract] [Full Text]

				B. Teicher, T. Herman, S. Holden, Y. Wang, M. Pfeffer, J. Crawford, and E Frei 3rd Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo Science, March 23, 1990; 247(4949): 1457 - 1461. [Abstract] [PDF]