Effect of lsonicotinic Acid Hydrazide on the lntratumor Injection of BeG" 2 Frank C. Sparks, 3 N. Erick Albert, 4 and James H. Breeding 5 ABSTRACT-Rats with established subcutaneous tumors were treated by repeated intratumor injections of BCG over a 5·week period. Isonicotinic acid hydrazide (IN H) was given to some rats to determine if this drug decreased the effect of BCG on local tumor growth. INH alone had no effect on either survival or tumor volume. Rats treated with either BCG or BCG and INH had prolonged survivals and smaller tumor volumes than did control rats. In these experiments, INH did not decrease the effect of BCG on local tumor growth. However, the intratumor injection of BCG in rats receiving INH systematically was associated with better survival and smaller tumor volumes compared to the intratumor injection of BCG alone.-J Natl Cancer Inst 58: 367-368,1977.
The intratumor injection of BCG can cause regression of intradermal deposits from malignant melanoma. In our experience this procedure is the treatment of choice in selected patients (1). The com plications of the intratumor injection of BCG can be significant (2-:D, and at least two fatalities have been reported (5). In most patients, INH promptly decreases the side effects. Gerner and Moore (6) suggested that INH be given prophylactically to all patients undergoing an intratumor injection of BCG. Even though this practice might decrease the adverse side effects of BCG, we suggested that it might also decrease the immunotherapeutic effects (7). Blanden et al. (8) reported that INH impaired nonspecific bacterial resistance and the development of delayed cutaneous hypersensitivity to PPD in BCG-infected mice. Zbar et al (9) showed that viable BCG organisms were needed to suppress tumor growth in guinea pigs; heat-killed BCG organisms were unable to suppress tumor growth. Chung et al. (10) studied the effect of INH in mice inoculated intradermally with a mixture of tumor cells and BCG. INH did not decrease the immunoprophylactic effect of BCG or change the incidence of delayed cutaneous hypersensitivity to PPD but it did significantly reduce the degree of delayed cutaneous hypersensitivity to PPD. Our experiments were done to determine if INH decreases the effect of an intratumor injection of BCG on an established tumor. MATERIALS AND METHODS
A 2-mm3 section of mammary adenocarcinoma 13762 (MT) was implanted sc in 55 F344 rats. In this tumor system, BCG prevents the growth of spontaneous metastases (11). Eleven days later, when the tumor diameter was 5 mm, rats were randomly divided into 4 groups. Group 1 (13 rats) received no further treatment. Group 2 (15 rats) had 0.1 ml BCG injected into the tumor three times per week for 2 weeks, then 2 times per week for 3 weeks for a total of 12 injections. Group 3 (2 rats) had INH injected ip 5 times per week for 5 weeks. Group 4 (15 rats) had BCG injected into the tumor as in group 2, and INH injected ip as in group 3. Drug doses were 10 7 Tice strain BCG and 30 mg INH/kg. Tumors were measured two to three times per week, and tumor volumes (V) calculated. Tumor growth curves were deterVOL. 58, NO.2, FEBRUARY 1977 Downloaded from https://academic.oup.com/jnci/article-abstract/58/2/367/1012850 by INSEAD user on 07 March 2018
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mined from a regression line of VI/3 versus time. Tumor volumes were then compared by multiple linear regres· sion analysis of the growth curves (12). Survival curves were compared by nonparametric analysis (13). Surviving animals were killed on day 86 and examined for the presence of tumor. RESULTS
Rats treated with BCG, alone and with INH, had increased survivals (P
The intratumor injection of BCG can cause regression of intradermal deposits from malignant melanoma. In our experience this procedure is the treatment of choice in selected patients (1). The com plications of the intratumor injection of BCG can be significant (2-:D, and at least two fatalities have been reported (5). In most patients, INH promptly decreases the side effects. Gerner and Moore (6) suggested that INH be given prophylactically to all patients undergoing an intratumor injection of BCG. Even though this practice might decrease the adverse side effects of BCG, we suggested that it might also decrease the immunotherapeutic effects (7). Blanden et al. (8) reported that INH impaired nonspecific bacterial resistance and the development of delayed cutaneous hypersensitivity to PPD in BCG-infected mice. Zbar et al (9) showed that viable BCG organisms were needed to suppress tumor growth in guinea pigs; heat-killed BCG organisms were unable to suppress tumor growth. Chung et al. (10) studied the effect of INH in mice inoculated intradermally with a mixture of tumor cells and BCG. INH did not decrease the immunoprophylactic effect of BCG or change the incidence of delayed cutaneous hypersensitivity to PPD but it did significantly reduce the degree of delayed cutaneous hypersensitivity to PPD. Our experiments were done to determine if INH decreases the effect of an intratumor injection of BCG on an established tumor. MATERIALS AND METHODS
A 2-mm3 section of mammary adenocarcinoma 13762 (MT) was implanted sc in 55 F344 rats. In this tumor system, BCG prevents the growth of spontaneous metastases (11). Eleven days later, when the tumor diameter was 5 mm, rats were randomly divided into 4 groups. Group 1 (13 rats) received no further treatment. Group 2 (15 rats) had 0.1 ml BCG injected into the tumor three times per week for 2 weeks, then 2 times per week for 3 weeks for a total of 12 injections. Group 3 (2 rats) had INH injected ip 5 times per week for 5 weeks. Group 4 (15 rats) had BCG injected into the tumor as in group 2, and INH injected ip as in group 3. Drug doses were 10 7 Tice strain BCG and 30 mg INH/kg. Tumors were measured two to three times per week, and tumor volumes (V) calculated. Tumor growth curves were deterVOL. 58, NO.2, FEBRUARY 1977 Downloaded from https://academic.oup.com/jnci/article-abstract/58/2/367/1012850 by INSEAD user on 07 March 2018
367
mined from a regression line of VI/3 versus time. Tumor volumes were then compared by multiple linear regres· sion analysis of the growth curves (12). Survival curves were compared by nonparametric analysis (13). Surviving animals were killed on day 86 and examined for the presence of tumor. RESULTS
Rats treated with BCG, alone and with INH, had increased survivals (P
