Increase in the effectiveness of melphalan therapy with progression of MOPC-315 plasmacytoma tumor growth

Abstract

Following inoculation with 1 X 10(6) MOPC-315 tumor cells, a single injection of a very low dose of melphalan (L-PAM, L-phenylalanine mustard), 0.75 mg/kg, cured most of the mice bearing a day 11 large primary tumor (20 mm) and metastases, but failed to cure mice bearing a day 4 nonpalpable tumor. Treatment of mice bearing a nonpalpable tumor with the very low dose of drug compromised the ability of the mice to respond effectively to the same low dose of drug when the tumor became large (day 12). However, a nonpalpable tumor could be eradicated by treatment of tumor bearers with a low dose of L-PAM, if it was present concomitantly with a large tumor on the contralateral side. A high dose of L-PAM, 15 mg/kg, cured mice bearing either a nonpalpable or a large tumor. The eradication of the tumor induced by the high dose of L-PAM appeared to be due solely to the tumoricidal effect of the drug. On the other hand, the eradication of the tumor by the low dose of L-PAM also required the participation of antitumor immunity of the host, since subsequent injection of antithymocyte serum abrogated the curative effect of the drug in most mice. Mice cured by a high dose of L-PAM were not resistant to subsequent lethal tumor challenge. In contrast, mice cured by the low dose of L-PAM were able to reject a tumor challenge of 300 times the minimal lethal tumor dose. The results obtained with L-PAM therapy are similar to the results that we had previously reported with cyclophosphamide therapy. Thus, the timing of therapy with a low dose of drug for mice bearing a MOPC-315 tumor is critical for successful therapy. Moreover, the selection of a low dose rather than a high dose of drug to eradicate a large tumor offers the advantage that it results in long-lasting potent antitumor immunity as a consequence of the participation of host antitumor immunity in the eradication of the tumor.

Melphalan and Other Anticancer Modalities Up-Regulate B7-1 Gene Expression in Tumor Cells

“…A fresh stock solution of L-PAM (Sigma, St. Louis, MO) was prepared as previously described (2). A dose of 2 mg/kg body weight (low dose) was administered i.p.…”

“…T he ability of anticancer drugs to facilitate the acquisition of antitumor immunity by tumor bearers has been recognized for quite some time (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). In fact, several anticancer drugs (e.g., cyclophosphamide (1, 4 -6, 8, 10, 11), L-PAM 4 (2), 1,3-bis(2-chloroethyl)-1-nitrosourea (7), vinblastine (9), and bleomycin (3)) have been shown to enhance the acquisition of T cellmediated antitumor responses in a variety of animal tumor models (1-3, 6 -9) and in patients with advanced melanoma (4,10,11) or advanced renal carcinoma (5).…”

“…We have recently initiated studies to elucidate the importance of B7-1 and B7-2 expression for L-PAM-induced acquisition of T cell-dependent tumor-eradicating immunity in hitherto immunosuppressed mice bearing a large MOPC-315 tumor (19). Specifically, we determined the effect of anti-B7-1 or anti-B7-2 mAb on the curative effectiveness of low-dose L-PAM for MOPC-315 tumor bearers under conditions in which the therapeutic outcome of the chemotherapy depends on the contribution of T cell-dependent immunity for tumor eradication (2,20,21). Our studies revealed that B7-1 and B7-2 are important for the curative effectiveness of low-dose L-PAM for MOPC-315 tumor bearers.…”

Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells

“…In an animal model, and in some clinical studies, cyclophosphamide, melphalan, N,N 0 -bis(2-chloroethyl)-N-nitrosourea, vinblastine, and bleomycin enhanced the acquisition of T-cellmediated antitumor immunity. [1][2][3][4][5][6][7][8][9][10][11] For example, in mouse lymphoma cells, DNA-alkylating agents alleviate silencing of class II transactivator gene. 12 Another possible mechanism could be the upregulation and/or neoexpression of costimulatory molecules or cytokines by tumor cells.…”

Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells

“…In a few experiments we used the MOPC-315 plasmacytoma, which under normal conditions is negative for B7-1 surface expression but expresses relatively high levels of B7-2 (15). MOPC-315 tumor cells were maintained in vivo, as previously described (15,19), in BALB/cAnNCrlBR mice 7-10 wk old, that were purchased from Charles River Breeding Laboratories (Wilmington, MA).…”