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N Wolmark

Publications and source records attributed to N Wolmark.

At least 127 records · Page 7Linked to original sources
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. II. Effect of cortisone acetate.

Studies from this laboratory have demonstrated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. A study of the effect of two different doses of cortisone acetate (CA), administered two or five times weekly, on the tumor inhibitory properties of this chemoimmunotherapeutic regimen indicated that the addition of a corticosteroid to the CY-CP combination did not alter its tumor-inhibitory properties. There was no significant change when CA was administered with CP; however, tumor inhibition was enhanced to a degree approaching statistical significance when CA was added to CY at dose levels of 1.5 and 2.5 mg twice weekly. These results demonstrated that it may be possible in treatment of humans to administer a steroid in combination with a chemoimmunotherapeutic regimen without inhibition of the regimen's antitumor effects.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. III. Effect of C. parvum on cyclophosphamide metabolism.

Results of investigations employing [14C]cyclophosphamide (CY) demonstrated that even though total plasma radioactivity was similar in female C3HeB/FeJ mice treated either with CY alone or Corynebacterium parvum and CY, the proportion of total activity due to nonmetabolized CY was greater when C. parvum was used. These findings indicated that the antitumor effect of C. parvum may not have been entirely due to its immunopotentiating properties but may also have been related to its effect on the metabolism of CY.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by corynebacterium parvum with cyclophosphamide.

The cytotoxic macrophage was further characterized as an important effector cell in the inhibition of tumor growth. When we administered rifampin (a semisynthetic antibiotic that interferes with macrophage function but not viability) with Corynebacterium parvum and/or cyclophosphamide to tumor-bearing C3HeB/FeJ female mice, the tumor growth-inhibitory effects of the C. parvum were reduced. Moreover, when bone marrow cells from those animals were cultured, we found a marked decrease in the cytotoxicity of macrophages comprising clonies arising from colony-forming cells (CFC) in the bone marrow. Such findings supported our contentions that 1) the cytotoxic property of macrophages originates in ancestral stem cells or CFC in bone marrow, and 2) receptor sites of the CFC (or stem cells) that respond to a stimulus for self-replication probably differ from sites that when activated produce progeny with cytotoxic properties. Although the administration of rifampin resulted in macrophages virtually devoid of cytotoxic properties, both relative and absolute numbers of CFC increased.

Animals↗
PubMed1976

Correlation of antitumor chemoimmunotherapy with bone marrow macrophage precursor cell stimulation and macrophage cytotoxicity.

The present investigations have assessed the effects of prolonged cyclophosphamide (CY) and Corynebacterium (CP) treatment on the production of bone marrow macrophage precursors [colony-forming cells (CFC)] and on the cytotoxicity of macrophages comprising colonies produced by the CFC. The findings have been correlated with tumor growth in animals receiving the immunochemotherapy. In addition, studies have been directed toward ascertaining whether the administration of CP with CY might lessen the myelosuppressive effects of the latter. Following each consecutive weekly dose of CY (even after as many as 11), there was a significant depression in the number of bone marrow cells (BMC's) but, by the next injection, marrow cellularity had returned to normal. When the number of BMC's was reduced, the proportion of the remaining cells, which consisted of CFC, was increased. Upon reconstitution of the marrow, the proportion of CFC returned to the level of the controls. The total number of CFC in marrow was at no time following CY therapy significantly less than the number in marrow of untreated mice. The addition of CP to the treatment regimen with CY resulted in an absolute as well as relative increase in CFC at all times during administration of the combined therapy, i.e., when there was a depression in total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total BMC's had been neither increased nor prevented from decreasing, by CP administration, indicating that the use of total cellularity as an index of the CP marrow-sparing effect is without merit. The present results relative to cytotoxicity of macrophages derived from the CFC concur with and extend our previous findings indicating that the cytotoxic property of macrophages originates in its ancestral stem cell or CFC and that factors responsible for increasing the CFC population do not selectively stimulate precursor cells responsible for production of the cytotoxic macrophage. Although the proportion of cytotoxic macrophages was not altered by CP when administered with CY, the absolute number of such cells was increased. Since the increase in macrophage colony production and, consequently, in cytotoxic macrophages correlates with increased inhibition of tumor growth when CP was used with CY, it is suggested that macrophage precursors are the cells of primacy in CP immunopotentiation. Their stimulation, resulting in enhanced cytotoxic macrophage formation, could be responsible for the inhibition of tumor growth observed in our model system. The findings also suggest that when myelosuppression is a limiting factor in the use of a chemotherapeutic agent, the concomitant use of CP may be advantageous.

Animals↗
PubMed1976

The effect of a growing tumor and its removal on the cytotoxicity of macrophages from cultured bone marrow cells.

Previous investigations by us have demonstrated that there is a significant but transient (4 to 14 days) increase of colony-forming cells (CFC) in bone marrow following implanation of a syngeneic mammary tumor in C3H mice. Those CFC gave rise to enhanced macrophage colony production when cultured in semisolid medium. The present studies have for the first time demonstrated that macrophages from the colonies were cytotoxic to cells from the immunizing tumor, and they continued to possess that characteristic for as long as a tumor was present in the animal from which bone marrow was derived. By 21 days after tumor removal cytotoxicity was no longer evident. The findings provide evidence to suggest that the cytotoxicity displayed by the macrophage originates in its ancestral CFC or in the antecedent stem cell. They also suggest that receptor sites of the CFC (or stem cell) that respond to a stimulus for self-replication are probably different from those sites that, when activated, result in cytotoxic properties of their progeny. The present findings also indicate not only that quantitation of macrophage production is of relevance in determining the efficacy of a therapeutic regimen but also that knowledge concerning the specific properties, i.e., ctytotoxicity, of such cells is of equal or greater importance.

Animals↗
PubMed1976

The effect of Corynebacterium parvum in combination with 5-fluorouracil, L-phenylalanine mustard, or methotrexate on the inhibition of tumor growth.

Previous reports from this laboratory have demonstrated conclusively that cyclophosphamide administered asynchronously with Corynebacterium parvum (CP) results in greater C3H mammary tumor inhibition than that observed with either agent alone. An analysis of this combination has revelaed that the chemotherapeutic component contributes more significantly to tumor inhibition than does the immunotherapeutic one. This study was conducted to investigate the inhibition of C3H mammary tumors by other chemotherapeutic agents when used with CP. The results have demonstrated that 60 mg of cyclophosphamide per kg, 90 mg of 5-fluorouracil per kg, and 10 mg of L-phenylalanine mustard per kg administrated weekly have similar tumor-inhibiting properties. The addition of CP enhanced the tumor-inhibiting properties of each agent but to differing degrees. The effect of the immunopotentiator when used in combination with alkylating agents was greater than that seen when it was used with the antimetabolite 5-fluorouracil. The tumor inhibition observed when cyclophosphamide was administered asynchronously with CP was significantly greater than that observed when L-phenylalanine mustard was similarly used. Of particular interest was the finding that the addition of CP to a combination of chemotherapeutic agents resulted in no greater tumor growth inhibition than that which occurred when CP was used along with the most effective single agent in the combination. The data have indicated that, contrary to clinical impression, there is no evidence that CP through its toxicity-sparing effect permits the utilization of larger doses of chemotherapy. Consideration has been given to the mechanisms that might account for the differences in tumor growth inhibition encountered when CP was used with different chemotherapeutic agents.

Animals↗
PubMed1975

L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings.

Prolonged l-phenylalanine mustard (L-PAM) administration as an adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically positive axillary nodes was evaluated by a prospective, randomized, clinical trial. Treatment failures occurred in 22 per cent of 108 patients receiving placebo and 9.7 per cent of 103 women given L-PAM (p = 0.01). A statistically significant difference (p = 0.02) existed in favor of L-PAM relative to disease-free interval. In premenopausal women, the difference with respect to disease-free interval of treated and control groups was highly significant (p = 0.008). A treatment failure occurred in 30 per cent of premenopausal patients receiving placebo and 3 per cent of those treated with L-PAM (p = 0.008). Whereas a similar trend was observed in postmenopausal patients, the difference is not statistically significant. Thus, L-PAM has been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those who are premenopausal. Results were achieved with minimal undesirable side effects.

Bone Marrow↗
PubMed1975

Inhibitory effect of prolonged Corynebacterium parvum and cyclophosphamide administration on the growth of established tumors.

The present study was carried out to investigate the effects of prolonged administration of C. parvum alone and in combination with cyclophosphamide for the treatment of established, measurable C3H tumors. The continued weekly administration of C. parvum by itself provided a limited but significant inhibitory effect on tumor growth and significantly prolonged survival. Intraperitoneal and intravenous administration was found to be more effective than the subcutaneous route. When C. parvum was administered asynchronously in combination with cyclophosphamide at weekly intervals a tumor growth inhibitory effect was achieved which was greater than that resulting from either agent along. Such an effect was consistently obtained and was seemingly independent of the sequence of drug administration. When cyclophosphamide preceded the initial C. parvum administration, arrest in the rate of tumor growth occurred, resulting in infinite tumor doubling time for the duration of observation (greater than 90 days). The combination of C. parvum and cyclophosphamide produced a more effective inhibition of tumor growth than did BCG and cyclophosphamide similarly employed. The importance of these findings relative to clinical application is considered. While the significance and genesis of the marked desmoplastic reaction characterizing tumors from animals treated with C. parvum and cyclophosphamide is at present speculative, consideration is given to the possibility that this could signify a host response against tumor growth.

Animals↗
PubMed1975

Studies concerning the regional lymph node in cancer. VIII. Effect of two asynchronous tumor foci on lymph node cell cytotoxicity.

Results suggest that cytotoxicity by cells from nodes regional to a primary tumor is unique. While a primary tumor was present, A) cytotoxicity was displayed by cells from lymph nodes (RLNs) to that tumor, B) cells from nonregional lymph nodes regional (NRLNs) possessed lesser cytotoxicity which failed to increase in response to a second tumor focus in an area drained by those nodes, and C) the second focus attenuated cytotoxicity of cells from LNs regional to the primary tumor. Following removal of the primary tumor, cells from RLNs rapidly lost cytotoxicity and with passage of time were unable to regain that function in response to a second tumor focus. In contrast, cells from NRLNs demonstrated increased cytotoxicity at any time following removal of the primary tumor when exposed to a second focus. These observations suggest that nodes regional to a distant metastatic focus may be unable to react to it and thus contribute little to the host response generated by the primary tumor. In addition, since nodes regional to a primary tumor manifest diminished cytotoxicity in the presence of a distant tumor focus, tumor cells gaining access and lodging in those nodes subsequent to the development of other metastatic foci are likely to proliferate, resulting in the "positive" lymph node. The findings are in keeping with our contention that host factors responsible for metastases, and perhaps metastases themselves, are at least in part responsible for growth of tumor in RLNs. They also have relevance to the site of administration of specific immunotherapeutic agents and to the significance of the removal of RLNs with a primary tumor.

Amputation, Surgical↗
PubMed1975

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. I. Variation in administration of both agents.

Studies from this laboratory have indicated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. The present investigations on optimal dosage, route, frequency, and sequence of administration of CY and CP in the model system were performed to obtain information that could be useful in the design of chemotherapeutic and immunotherapeutic regimens for the treatment of human tumors. Findings have suggested the need for administration of CP in more than one instance. Although a single dose of CP in combination with weekly injections of CY had a significantly prolonged inhibitory effect, weekly doses of CP and CY were more effective. We also concluded that the time between doses of an immunostimulating agent (I-I interval) as well as between administration of chemotherapy (C-C interval) may be critical for an optimal result. In this model system, C-C and I-I intervals of 7 days inhibited tumor growth most effectively. The time between administration of chemotherapy and immunotherapy (C-I interval) has been considered critical. Whereas slightly better results were achieved in these studies when the immunotherapy was administered 4 days after the CY or when the C-I interval was +4 days, almost equally good results were obtained when both agents were given on the same day, which signified that the C-I interval may not be as critical as other investigators have reported. The present findings confirmed and extended our prior observations and indicated that the iv and ip routes of administration were superior to the im and sc routes in our model. The observed tumor growth inhibition was a result of both chemotherapeutic and immunotherapeutic modalities; also, the inhibitory properties of the regimen were more related to the chemotherapeutic component. Finally, almost identical tumor growth inhibition was observed when CP obtained from two different laboratories was used in conjunction with CY.

Animals↗
PubMed1975

Ten year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy.

In 1958, a co-operative clinical trial, involving 23 institutions, was begun to evaluate the efficacy of a short course of triethylenethiophosphoramide as an adjuvant to radical mastectomy in the treatment of patients with primary carcinoma of the breast. Of 826 women prospectively randomized so that they received either a placebo or triethylenethiophosphoramide, 99.3 per cent were available for five years of follow-up study, and 95.3 per cent have been observed for ten or more years. Results have indicated the inadequacy of standard operative therapy in effecting a permanent tumor-free state in a majority of patients. Particularly distressing was the finding that 76 per cent of all patients with positive axillary nodes--65 per cent with one to three and 86 per cent of those with more than or equal to four positive--demonstrated a treatment failure by ten years and that only 24.9 per cent survived. The survival rate of those with one to three positive nodes was 37.5 per cent and only 13.4 per cent if more than or equal to four nodes contained tumor. Also disturbing was the observation that one of four patients with negative axillary nodes displayed a treatment failure by ten years. Such findings mandate the urgency for immediate evaluation of available systemic therapeutic agents postoperatively. That systemic chemotherapy can enhance the disease-free state as well as survival rate of at least some patients with carcinoma of the breast is supported by the finding that the original observation at 18 months indicating an advantage for premenopausal women with more than or equal to four positive nodes who received triethylenethiophosphoramide persisted for as long as ten years. At that time, 21 per cent fewer patients in the triethylenethiophosphoramide group had treatment failures and 21 per cent more survived, an indication that the initial delay in treatment failure was reflected in patient survival rate. Data suggesting that the limited chemotherapy used was more effective in patients having smaller tumors are in keeping with the concept that adjuvant therapy is likely to be most effective in a host with minimal residual tumor burden. Of importance was the observation that 80 per cent of treatment failures occurring in ten years were apparent by five years of observation. Strikingly, 86 per cent of ten year treatment failures in patients with positive nodes occurred by five years. In patients with more than or equal to four positive nodes, this was so in 92 per cent of the instances. Such findings tend to discredit the claim that the worth of an alternative treatment for carcinoma of the breast can be ascertained only by a period of observation much longer than five years.

Adult↗
PubMedDate not supplied

Acute toxicity during adjuvant chemotherapy for breast cancer: the National Surgical Adjuvant Breast and Bowel Project (NSABP) experience from 1717 patients receiving single and multiple agents.

Since 1972, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has carried out a series of clinical trials evaluating the worth of adjuvant chemotherapy in the management of patients with primary breast cancer. This report provides information concerning (a) protocol compliance relative to drug administration and (b) acute toxicity encountered by patients in three separate trials who were given one-, two- or three-drug chemotherapy within 1 month of operation. The findings are derived from 1548 women who received 20,765 courses of chemotherapy, the most extensively documented experience yet reported. They indicate that despite the large number of physicians and the heterogeneity of the institutions participating, large cooperative efforts can be accomplished with credibility. Only 13 (0.8%) of the women failed to complete all courses of therapy for reasons directly related to nonprotocol compliance by physicians. Only 4.3% failed to complete therapy for miscellaneous reasons other than toxicity, treatment failure, occurrence of a second primary, or death unrelated to tumor. While almost all patients experienced toxic reactions during the therapy, only 3%--4% of recipients of melphalan (L-PAM; P) and 4%--5% of recipients of L-PAM + 5-FU(F)(PF) failed to complete 2 years of therapy because of toxicity. Of those patients receiving PF + methotrexate (MTX; M) (PMF), 15% did not finish their treatment for that reason. While there was little difference in hematologic and nonhematologic toxicity between those patients receiving P or PF, and such toxicity was generally acceptable to both patients and physicians, the addition of MTX (PMF) resulted in greater toxicity (vomiting, stomatitis, and alopecia) which was less readily accepted. Tolerance of any of these regimens was unrelated to patient age, despite the belief that older women are less tolerant of chemotherapy. The earlier toxicity occurred, the greater was the number of subsequent courses associated with toxicity, and the lower was the total amount of drug received. The extent of the toxicity produced by the NSABP regimens and the end results obtained with them, must be compared with the end results and toxicity obtained by other regimens before making a choice of the adjuvant therapy to be used.

Aged↗