Frank M. Schabel

Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas.

Single agents and combinations of agents were tested for antitumor activity against four transplantable colon tumors in mice. The most impressive anti‐tumor activity was obtained with anguidine and the combination of anguidine + 5‐FU against colon adenocarcinoma No. 38. Antitumor potentiation was obtained when the combination was injected simultaneously on a Q7d schedule (two experiments), but not on an alternating schedule of administration (3 or 4 days separating injections of the two agents). Anguidine was highly active only in a colon tumor that was very responsive to 5‐FU. The correlation between high 5‐FU sensitivity and high anguidine sensitivity may be coincidental or could be of predictive value. Other active single agents and combinations of agents against one or more of the colon tumors include 5‐FU, 5‐FUdR, MeCCNU, BCNU, homoharringtonine, ara‐C, Cis‐Pt‐II, dianhydrogalactitol, piperazinedione, cyclophosphamide; MeCCNU + 5‐FU; Adriamycin + 5‐FU; Adriamycin + cyclophosphamide; Adriamycin + palmO‐ara‐C; cyclophosphamide + procarbazine; and 5‐FU + palmO‐ara‐C. (The combination of 5‐FU + palmO‐ara‐C was potentiating only on an alternating schedule.) The results of surgery‐chemotherapy adjuvant treatment of metastatic colon tumors established that if an agent or a combination was highly active against moderately advanced tumor masses, this treatment was also highly active after surgery against residual metastatic disease. The converse was also true. That is, if the agent or combination was inactive or marginally active against moderately advanced disease, the treatment was also relatively ineffectual after surgery against residual metastatic disease. Based on surgical‐adjuvant experiments with colon tumor No. 26, the following agents and combinations are conditionally recommended: MeCCNU + 5‐FU; MeCCNU + Ara‐C; cyclophosphamide + Ara‐C; BCNU+ 5‐FU and MeCCNU. It is also assumed that those agents active against the advanced disease are likely to be active after surgery against residual metastatic cells. Thus, agents highly active against advanced‐stage colon adenocarcinoma No. 38 are possible candidates for adjuvant therapy. On this basis, anguidine and anguidine + 5‐FU are recommended.

Patterns of Resistance and Therapeutic Synergism among Alkylating Agents1

Alkylating anticancer drugs are varied in chemical structure, alkylating moieties, and likely mechanisms of cytotoxic activity for vital normal cells and sensitive tumor cells. This has been objectively documented by numerous examples illustrating: (1) different in vitro and in vivo reaction products; (2) greater than additive, additive, and less than additive cytotoxicity of drug combinations for vital normal cells in the mouse; (3) readily reproducible and often marked therapeutic synergism between a variety of 2-drug combinations of alkylating agents against a wide variety of histologic types of murine tumors, and (4) observed resistance and cross-resistance of a variety of murine tumors, selected for resistance to specific alkylating agents, compatible with recognized chemical and functional differences between these drugs. The most important observations on resistance and cross-resistance reported are: (a) L1210 cells selected for complete resistance to cyclophosphamide (CPA) retain full sensitivity to selected nitrosoureas (BCNU, CCNU, MeCCNU), chlorozotocin), dianhydrogalactitol, and cis-DDPt, while retaining marked but somewhat reduced sensitivity to L-PAM, piperazinedione, and thioTEPA. (B) L1210 cells selected for resistance to BCNU retain full sensitivity to CPA, L-PAM, and dianhydrogalactitol. They show complete cross-resistance to BIC and variable cross-resistance to other selected nitrosoureas and piperazinedione. (c) L1210/L-PAM has incomplete but marked resistance to L-PAM. It is similar to the parent drug-sensitive line (L1210/0) in response to BCNU, CCNU, MeCCNU, and BIC. It is variably (usually moderately) cross-resistant to CPA, chlorozotocin, dianhydrogalactitol, and thioTEPA, but is completely cross-resistant to cis-DDPt. These resistance and cross-resistance patterns, which are consistent with most other biological and chemical principles established with these alkylating agents, may be useful in selecting alkylating drug combinations for inclusion in chemotherapy protocols in man which, on the basis of diverse observations in animal tumor systems, appear to be clearly indicated.

Rationale for adjuvant chemotherapy

Surgery or radiation therapy fails to cure clinically evident human cancer, in the main, if the disease is systemic (has metastasized) when first recognized, because neither modality can effectively remove or kill distant and/or unrecognized metastases. Starting drug treatment of a tumor when it is first clinically recognized, or when it re‐presents following noncurative surgical or radiological treatment, fails to cure over 90% of cancer in man because the body burden of tumor cells exceeds the tumor cell kill potential of nearly all of the most effective drugs or drug combinations against most tumors. The indicated approach to improving cure rates under these circumstances is to use chemotherapy as an adjuvant to effective (life‐prolonging) but noncurative surgical and/or radiological treatment. Surgical adjuvant chemotherapy of carcinoma of the breast and osteogenic sarcoma has already been shown to increase the disease‐free interval over that obtained with surgery alone, and the probability of having achieved significant increases in long‐term cure rates is high. Laboratory studies with transplantable metastatic lung, breast, and colon carcinomas and melanotic melanoma, and with a spontaneous breast carcinoma of mice, all of which are uniformly fatal if untreated, have shown that: 1) the incidence of metastatic disease is directly related to tumor mass, 2) surgical cure rates drop as tumor mass at surgery increases, 3) grossly evident primary tumors are generally not curable by drug treatment, and 4) surgical adjuvant chemotherapy increases the long‐term cure rates with all of these tumors and significantly increases the life span of treatment failures. Effective surgical adjuvant chemotherapy is both dose‐responsive and related to the body burden of metastatic tumor at time of drug treatment. The effectiveness of surgical adjuvant chemotherapy decreases 1) as the tumor staging is advanced prior to surgery, 2) as the interval from surgery to start of effective chemotherapy is increased, and 3) as the drug doses are reduced. Additionally, and of critical importance to treatment planning, some drugs that are marginally effective or ineffective against the presurgical total body burden of tumor cells are curative in some to all mice with metastatic disease if given shortly after surgical removal of the primary tumor.

Surgical adjuvant chemotherapy of metastatic murine tumors.

Surgery or radiation therapy fails to cure clinically evident cancer, in general, if the disease is systemic when first recognized, because neither modality can effectively remove or kill distant and/or unrecognized metastases. Drug treatment beginning at first clinical recognition fails to cure over 90% of cancers, systemic or not, because the body burden of tumor cells exceeds the tumor cell kill potential of most of our best drug treatments. The indicated approach to improving cure rates under these circumstances is combined‐modality treatment. Surgical adjuvant chemotherapy of both osteogenic sarcoma and carcinoma of the breast has already been shown to increase the disease‐free interval over that obtained with surgery alone, and the probability of having achieved significantly increased long‐term cure rates is high. A number of transplantable metastatic murine tumors (lung, breast, colon, melanoma) which are uniformly fatal following subcutaneous implant have been studied at Southern Research Institute. The incidence of metastatic disease is directly related to tumor mass. Surgical cure rates drop as primary tumor mass at surgery increases. Grossly evident primary tumors are generally not curable by drug treatment. Surgical adjuvant chemotherapy has been shown reproducibly to increase the long‐term cure rates of all of these tumors and increase the life span of curative failures significantly. Effective drug therapy in the surgical adjuvant setting is both dose‐dependent and related to body burden of metastatic tumor at the time of drug treatment. Some drugs that are apparently ineffective against the presurgical total body burden of tumor cells are curative in some to all mice with metastatic disease if given shortly after surgical removal of the primary tumor. Examples of these several tumor systems and results of combined modality treatments are shown. Cancer 40:558–568, 1977.

Studies on the mode of action of azaserine

Abstract 1. 1. Azaserine-induced inhibition of E. coli was significantly prevented by (a) 4-amino-5-imidazolecarboxamide (AIC), adenine, guanine, hypoxanthine, or xanthine; (b) methionine; and (c) glutamine; and, as has already been observed by others, by phenylalanine, tyrosine, or tryptophan. 2. 2. In studies carried out on the effect of azaserine on purine synthesis in the tumors, intestines, livers, and spleens of mice bearing Sarcoma 180, it was found that azaserine inhibited utilization of formate-C14 and glycine-1-C14 for purine synthesis, failed to affect utilization of C14-labeled adenine, AIC, and hypoxanthine, and failed to affect utilization of formate for thymine biosynthesis. Azaserine also inhibited utilization of formate-C14 and glycine-1-C14 for purine synthesis by heterologous implants of a human sarcoma growing in the rat. 3. 3. The results indicate that azaserine inhibits purine synthesis in the intact animal at a stage prior to the formation of 5-amino-4-imidazole-carboxamide ribotide.

3-Deazauridine: Inhibition of Ribonucleic Acid Virus-Induced Cytopathogenic Effects In Vitro

3-Deazauridine, a synthetic analogue of uridine and a potential antitumor agent, was found to possess antiviral activity against a number of ribonucleic acid-containing animal viruses in mammalian cell culture. Inhibition of virus-induced cytopathogenic effects by 3-deazauridine was observed in cells infected with rhinovirus types 1A and 13, coxsackievirus type A21, and PR-8 influenza virus, but not in cells infected with poliovirus type 2 or echovirus type 12. The extracellular yield of progeny influenza virus was found to be significantly reduced in titer in 3-deazauridine-treated Madin-Darby canine kidney cell cultures at 12 to 24 hr after infection. Although the precise biochemical mechanism of action of this antimetabolites antiviral activity is not known, the compound does not appear to exert a direct virucidal effect on the influenza virion itself.

Purine analogs as potential anticytomegalovirus agents.

Summary The activity of 25 purine analogs was determined against human cytomegalovirus in vitro. Nineteen compounds were considered to have a degree of antiviral activity with seven of them markedly inhibiting both virus-induced cytopathogenic effects in WI-38 cells and the development of detectable virus. These seven compounds were 2-amino-9-β-d-ribofuranosyl-9H-purine-6-thiol, 2-aminopurine-6-thiol, 9-β-d-arabinofuranosyladenine, purine-6-thiol hydrate, purine-6-carboxaldehyde thiosemicarbazone, 2-amino-6-[(1-methyl-4-nitroimidazol-5-yl) thio] purine, and 9-β-d-ribofuranosyl-9H-purine-6-thiol. The active thiopurines protected the cells from virus infection if allowed to incubate with the cells 1 hr prior to addition of the virus. None of the compounds had demonstrable virucidal activity.

Anticancer Activity of Purine Antagonists and Their Ribosides. I. Comparative Studies with 6-Mercaptopurine and 6-Mercaptopurine Riboside.

Summary (1) 6-Mercaptopurine riboside has been assayed for inhibitory activity against Adenocarcinoma 755 in mice and has been found to be of approximately the same activity as 6-mercaptopurine. (2) Lines of S. faecalis resistant to 6-mercaptopurine have been found to be cross-resistant to 6-mercaptopurine riboside. (3) A line of Adenocarcinoma 755 selected for resistance to 6-mercaptopurine showed cross-resistance to 6-mercaptopurine riboside.

Observations on antiviral activity of netropsin.

Summary Netropsin, an antibiotic from culture nitrates of Streptomyces netropsis, has marked therapeutic effect on experimental vaccinial infections (WR strain) in intracerebrally inoculated mice. It is ineffective against infections in mice with the viruses of feline pneumonitis, influenza, Western equine encephalomyelitis, and poliomyelitis.

Therapeutic activity of mitoxantrone and ametantrone against murine tumors

Abstract Dr Schabel had intended to give this paper at the 13th International Chemotherapy Congress in Vienna but collapsed and died moments before he was due to deliver it. He had previously sent an abstract of the paper and copies of the slides with which he was going to illustrate it to one of the editors of Cancer Treatment Reviews and it was therefore possible to represent here the substance of the paper he could not give. For all those who knew Frank Schabel, his sudden death on Tuesday, 30 August 1983 came as a great shock. A memorial service in the presence of his widow and son was held for him in the Hofburg the following day. It was attended by many of his friends from the field of experimental cancer chemotherapy in which he toiled with such dedication and in which he made so many notable contributions. Moving addresses were given by K. Karrer, A. Goldin, J. Holland, E. J. Freireich and J. Montgomery.