The effectiveness of a relatively low dose of
cyclophosphamide (15 mg/kg CY),
melphalan (2.5 mg/kg
L-PAM) or the monofunctional form of CY (150 mg/kg MoCY) for the cure of mice bearing a large primary s.c. MOPC-315
tumor and extensive
metastases has been shown to be dependent on the cooperation of the drugs' tumoricidal activity with T-cell-dependent antitumor immunity, the latter facilitated by the
drug's immunomodulatory activity. Here, we have compared the curative effectiveness of three additional drugs: methyl nitrosourea (MNU),
hydroxyurea (
OH-
urea) and bis-chloroethyl nitrosourea (
BCNU). Among these drugs, only a relatively low dose of
BCNU (15-20 mg/kg) was effective in curing most mice (85%) bearing a large, late stage
tumor. A higher dose of
BCNU (40 mg/kg, LD10) was much less effective. After an optimal dose of
BCNU, the proliferative capacity of the
tumor cells 24 h after
therapy was reduced by greater than 97%. However, viable tumorigenic cells were still present in the primary
tumor and enhanced T-cell-dependent antitumor immunity was necessary for their eradication. The cured mice were resistant to
tumor rechallenge. When a low curative dose of
L-PAM was followed by
OH-
urea, the therapeutic effectiveness was not affected, but when this dose of
L-PAM was followed by a high nontoxic dose of MNU (100-150 mg/kg), the therapeutic effectiveness was diminished even though MNU was highly tumoricidal (i.e. greater than 99% inhibition of proliferative activity). Thus,
BCNU appears to be similar to CY,
L-PAM and MoCY in its mechanism of MOPC-315
tumor eradication. The alkylating activity of CY,
L-PAM, MoCY and
BCNU appears to be critical for their combined tumoricidal and immunomodulatory effects. Since
BCNU is the simplest of these four drugs with respect to metabolic pathway, a further study with
BCNU and related constructs may shed some light on the biochemical mechanisms of their mode of action. At least one reason for the ineffectiveness of
OH-
urea or MNU at either low or nontoxic high doses was poor tumoricidal or immunomodulatory activity, respectively. Thus, it seems important to consider both the tumoricidal and immunomodulatory activities of drugs when developing regimens for effective
chemotherapy.