William T. Bradner

ANTITUMOR ACTIVITY OF PLATINUM ANALOGS

Publisher Summary The antitumor drug cis-diamminedichloro platinum II (cis-DDP) is clinically active against many different neoplasms, most particularly bladder, ovarian, and testicular carcinomas. The drug, however, is not without its undesirable toxic side effects, which include renal toxicity, myelosuppression, and severe nausea and vomiting. In an attempt to improve upon the antitumor activity and/or lessen the unwanted toxic manifestations associated with using cis-DDP, many investigations have been undertaken to evaluate the analogs of this drug. Experimental studies involving platinum analogs have focused on the comparison of antitumor activity, toxic side effects, effectiveness in combination chemotherapy, and absence of cross-resistance. Several analogs have been found to have greater experimental antitumor activity than cis-DDP when evaluated against L1210 leukemia or ADJ/PC6 plasma cell tumor, and several congeners with 1, 2 diamino cyclohexane (DAC) substitutions have shown no cross-resistance to lines of P388 and L1210 leukemia resistant to cis-DDP. Clinical investigations involving some of the more active platinum analogs are also planned. The chapter presents the results of the testing of 74 analogs of cis-DDP for comparative antitumor activity in one to three experimental tumor systems.

4 Platinum Antitumour Agents

Publisher Summary This chapter focuses on platinum antitumor agents. Biologically active platinum complexes have been under investigation for nearly two decades. The large data base on structure–activity relationships has revealed a number of principles as well as raised new questions. Mechanistically, the aquation of the compounds and their ability to cause intrastrand cross-links in defined regions of DNA appear to be the chemical events most closely associated with antitumour activity. The reaction kinetics of the compounds in aqueous systems, which may be influenced by chelate effects, steric hindrance of bulky ligands or metal oxidation state have been studied for some complexes and are amenable to reasonably precise investigation in the future. The pharmacological behavior of the complexes in animals and in humans is, however, much less well defined. Although the pharmacokinetics of a number of compounds have been studied, conclusions regarding toxic effects have only been inferred, and reasons for varying antitumour effects are even less well understood. With intense motivation, both from the oncologic and commercial communities for clinical success, attention is heavily focused on the most active compounds in terms of antitumour effects.

TOXIC SIDE EFFECTS OF PLATINUM ANALOGS

Publisher Summary cis-Diamminedichloroplatinum II (cis-DDP) has been shown to be clinically effective alone or in combination against a variety of tumors such as testicular, ovarian, head and neck, and bladder. The effectiveness of cis-DDP has generated considerable interest in developing new platinum analogs with improved clinical profiles. The toxic side effects of cis-DDP include nephrotoxicity, nausea and vomiting, myelosuppression, and ototoxicity. The platinum analog programs are basically concerned with developing platinum compounds with reduced toxic side effects, especially nephrotoxicity and improved antitumor activity and spectrum. The chapter discusses a study to screen the platinum analogs for the side effects associated with cis-DDP. Side effects profiles were generated and were used in conjunction with the antitumor activity profiles to identify the most interesting analogs.

The mouse as a model for predicting the myelosuppressive effects of anticancer drugs

SummaryWe evaluated 17 clinically used anticancer drugs for their effects on total WBC and absolute neutrophil counts in BDF1 mice. These drugs were selected from three categories, based on their myelosuppressive effects in man: myelosuppression is dose-limiting; myelosuppression occurs but is not dose-limiting; or myelosuppression does not occur. The ability of each drug to cause myelosuppression in mice was determined by its effect on the neutrophil count 4 days after single-dose treatment. The neutropenic effect of the maximum tolerated dose (LD0–20) of each drug was characterized as marked (>65%↓), moderate (35%–65%↓), or minimal (<35%↓) to correspond with the three clinical categories of myelosuppression. The neutropenic effects in mice correctly predicted (true + or true-) the myelosuppressive effects in man for 13 of the 17 drugs (76%). Marcellomycin and the platinum complexes cisplatin, carboplatin, and spiroplatin did not cause neutropenia at maximum tolerated doses. These represent false-negative predictions, since the drugs are myelosuppressive in man. The results with the platinum complexes inducate that this method is not suitable as a means of screening these agents fior myelosuppression. Excluding the platinum complexes, the predictions were correct for 12 of 13 drugs (92%). Therefore, this model is considered a good predictor for the myelosuppressive effects of anticancer drugs in man (except platinum complexes) and can be used effectively to screen drugs for this toxicity. However, it is important that drugs identified by this system as being less myelosuppressive than the reference agent(s) be evaluated further, since all the incorrect predictions were false negatives.

Tallysomycin S10b: Experimental antitumor activity and toxicity

SummaryTallysomycin S10b (TLM S10b), a structural analog of bleomycin (BLM), was evaluated and compared with BLM for antitumor activity in several murine tumor systems and for toxic effects in mice and rats. Neither TLM S10b nor BLM was effective against IP P388 and L1210 leukemias, whereas both drugs were active against IP P388/J leukemia (a BLM-sensitive subline). TLM S10b and BLM were both active against murine solid tumors, including SC B16 melanoma, IV Lewis lung carcinoma, SC Madison 109 lung carcinoma, SC CD8F1 mammary carcinoma and SC Colon 38 carcinoma. In human tumor xenograft models, TLM S10b was active against a colon tumor and had slight activity against breast and lung tumors. Compared with TLM S10b, BLM had less activity against the colon tumor, comparable activity against the breast tumor, and no effect against the lung tumor. A consensus of the antitumor data indicated that compared with BLM, TLM S10b had comparable or greater activity and was about twice as potent. TLM S10b and BLM had approximately equivalent LD50 values in mice. TLM S10b had minimal effects on WBC counts, blood urea nitrogen levels, and serum glutamic pyruvic transaminase levels in mice during the time periods monitored. These effects were comparable to or less pronounced than those of BLM. Both drugs caused dose-related increases in the whole-lung hydroxyproline content in mice, but the dose-response curves were not parallel. TLM S10b caused a larger increase than BLM at the lower doses and a smaller increase than BLM at the highest doses. In rats, TLM S10b and BLM caused comparable, significant decreases in lung mechanics; however, histopathological examination of the lungs indicated that TLM S10b caused less evidence of pulmonary toxicity than did BLM at comparable dose levels. TLM S10b was, therefore, generally comparable to BLM in causing pulmonary toxicity in mice and showed possibly less pulmonary toxicity in rats, while demonstrating approximately equivalent to four-fold greater potency, depending on the test system. It also appeared that TLM S10b caused less pulmonary toxicity than BLM in both mice and rats at doses approaching maximally tolerated levels. TLM S10b is currently undergoing phase I clinical evaluation.

Phase I trial of FK973 : description of a delayed vascular leak syndrome

SummaryFK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3–4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drugs clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent

SummaryBMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 μg/kg per injection with consecutive daily (qd1-9) administration, to 51.2 μg/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic

SummaryBMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of < 0.02 to 3.25 μg/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDFBMY-28090 is also known as elsamicin, elsamicin A and BU2478A. mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing > 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines. Moreover, BMY-28090 had in vivo antitumor activity against murine leukemias, murine solid tumors and human tumor xenografts, including tumors located distal to the site of drug administration.

Antitumor activity of some microbial and chemical transformation products of anguidine (4,15-diacetoxyscirpene-3-ol).

SummaryThe in vivo antitumor activities, as measured by inhibition of transplanted P-388 and L-1210 leukemia in mice, have been determined for a series of analogs of anguidine including triacetoxyscirpenol, the three diacetoxyscirpenols, the three monacetoxyscirpenols, and scirpenetriol. An acetoxy function at position 15 appears to be required for good activity.

Synthesis and biological activity of 6-substituted mitosene analogues of the mitomycins

A series of 1-acetoxymitosene analogues, in which the substituent at C-6 was varied, was prepared by total synthesis and screened for activity against P388 leukemia in mice and induction of lambda phage in Escherichia coli. Among the 6-substituents prepared, none was as effective as the methyl group in conferring biological activity. However, certain N-methylcarbamates were more active than the unsubstituted carbamates.