melphalan and 4-hydroxycyclophosphamide

A preliminary analysis of our double high-dose chemotherapy with stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross-resistant studies, suggested that melphalan (M) adversely affected response to subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might affect response. We, therefore, constructed and examined preclinical models to determine whether prior exposure to M, in fact, adversely affected response to other therapy.. The purpose of the study was to determine whether the sequence of AAs, specifically the prior use of M, adversely affected response to subsequent treatment.. The methods employed were the following: (1) Human tumor cell lines rendered resistant by in vitro sequential exposure to five different AAs were developed. The resistant cell lines were examined for cross-resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer. (4) The double transplant model was developed in the mouse and the sequence of high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) studies of the various resistant tumor cell lines.. (1) The in vitro human tumor cells resistant to M were cross-resistant in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to other agents in only 10 to 20% of tests. (2) The in vivo studies of p388 indicated that resistance to M commonly crossed to other AAs and many non-AAs. (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs again indicated that M employed first markedly reduced responsiveness to subsequent treatment, particularly with AAs. (4) The double transplant model: again, M first markedly reduced response to other agents. (5) The in vitro resistant human tumor cell lines, particularly the breast cancer cell line MCF7, were found to contain high concentrations of glutathione S1 transferase gamma, which is consistent with that mechanism being responsible for resistance.. The sequence of alkylating agent treatment may substantially influence response. Melphalan, particularly, produces resistance that commonly crosses to the other AAs. Mechanistic studies indicate significant changes in glutathione S1 transferase, a known mechanism for broadly based resistance to AAs.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Breast Neoplasms; Carmustine; Cell Survival; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Mechlorethamine; Melphalan; Mice; Neoplasms, Experimental; Tumor Cells, Cultured

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for chemosensitivity testing. Currently, chemotherapy of gynecologic cancers remains controversial and empirical. To optimize the patient's chance of survival and to justify related toxicities, the chemoregimen should be individualized and based on the patient's chemosensitivity profiles. This study was performed to identify a panel of active drugs against uterine cancer cell lines for possible use in future chemosensitivity testing. We used the ATP chemosensitivity assays to screen 12 common cytotoxic agents against six uterine cancer cell lines. Drug concentrations required for a 50% surviving fraction were defined as IC50s. When using an IC50 of 0.21 PPC (peak plasma concentration) as a cutoff value for sensitivity, the following 8 drugs were considered effective for uterine cancer cell lines: actinomycin D, Adriamycin, vinblastine, etoposide, 5-fluorouracil, methotrexate, cytosine arabinoside, and mitomycin-C. Meanwhile, 4 drugs, cisplatin, 4OH-Cytoxan, bleomycin, and Alkeran with mean IC50s of 2.1 +/- 0.7, 0.8 +/- 0.1, greater than 5.0, and 0.75 +/- 0.36 PPC, respectively, were considered inactive or partially active with higher IC50s than peak plasma concentrations. In conclusion, the above panel of promising drugs can be further tested in animal models or human cancer specimens for possible use in chemosensitivity testing of uterine cancer patients.

Topics: Adenocarcinoma; Adenosine Triphosphate; Alkaloids; Antineoplastic Agents; Cisplatin; Cyclophosphamide; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; Intercalating Agents; Kinetics; Luminescent Measurements; Melphalan; Mitomycin; Tumor Cells, Cultured; Uterine Neoplasms

Premature chromosome condensation was induced by cell fusion in stimulated human lymphocytes treated with different cytostatics. Changes in the proportion of the cell-cycle stages were investigated after 72 h of culture. Although it has been reported that some agents which induce severe DNA damage accumulate cells in G2, our results have shown some differences in the modes of action of the different tested chemicals. These variations could be due to several factors like mechanisms of action of the drugs, sensitivity of lymphocyte subpopulations to the cytostatics, inter- and intra-individual variability in the response of donors.

Topics: Cell Cycle; Cell Fusion; Cell Line; Cells, Cultured; Chromosomes; Cisplatin; Cyclophosphamide; Humans; Lymphocyte Activation; Lymphocytes; Melphalan; Mitomycin; Mitomycins; Phytohemagglutinins